Therapeutic hydroxypyridinones, hydroxypyrimidinones and hydroxypyridazinones

ABSTRACT

The invention provides compounds of formula (I): and salts and prodrugs thereof wherein R4, X1 and X2 have any of the meanings defined in the specification, as well as pharmaceutical compositions comprising the compounds or salts and methods for their use in therapy. The compounds have useful antiviral properties.

BACKGROUND OF THE INVENTION

Influenza A infects a wide range of avian and mammalian hosts. Theconstant ability of the virus to evolve requires reformulation ofseasonal influenza vaccines on a yearly basis. The virus has eightgenomic RNA segments; reassortment of genomic RNAs from differentstrains and subtypes of influenza A is responsible for sporadicemergence of pandemic flu (Palese, P.; Shaw, M. L. Orthomyxoviridae: TheViruses and Their Replication. In Fields Virology, 5th ed., 2001; andKnipe, D. M., Howley, P. M., Eds.; Lippincott Williams & Wilkins:Philadelphia, Pa., 2007; Vol. 2, pp 1647-1689). Alternatively, all eightgenomic RNAs may be derived from an avian virus, and such a progenitorvirus then undergoes multiple mutations in the process of adapting to amammalian host (Taubenberger et al., Nature. 2005; 437(7060): 889-93).

Antivirals are used for both prophylactic and therapeutic treatments ofinfluenza infection. The available treatment options for influenza arelimited. Current antivirals are directed against the M2 ion-channelprotein (adamantanes) and neuraminidase (zanamivir and oseltamivir). Theadamantane drugs, amantadine and rimantadine, are ineffective due toemergence of resistance (predominantly through a M2 mutation, S31N) andthese drugs, in general, are not in clinical use. The neuraminidase(NA)-inhibiting oral drug, oseltamivir (Tamiflu) is widely used fortreating flu. Oseltamivir-resistant seasonal influenza A strains havebeen circulating for several years (Moscona, N Engl J Med. 2005;353(25):2633-6). The mutant viruses predominantly contain the NA H274Ymutation. When accompanied by compensatory mutations, the mutant virusesexhibit fitness comparable to wild-type influenza A and remain resistantto oseltamivir (Bloom et al., Science. 2010; 328(5983):1272-5). Thesemutations can emerge in almost all influenza A subtypes/strains,including the pandemic 2009 H1N1 virus (Memoli et al., J Infect Dis.2011; 203(3):348-57), resulting in a major concern for an effectivetreatment of flu. Therefore, new drugs are essential for treatingdrug-resistant and future pandemic flu strains.

Influenza A contains eight negative-stranded RNA genomic segments. Thethree largest genomic RNA segments encode the viral RNA-dependent RNApolymerase (RdRP) proteins consisting of the polymerase acidic protein(PA) and polymerase basic protein 1 (PB1) and 2 (PB2) subunits. The PAsubunit: (i) has endonuclease activity (ii) is involved in viral RNA(vRNA)/complementary RNA (cRNA) promoter binding, and (iii) interactswith the PB1 subunit (reviewed by Das et al., Nat Struct Mol Biol. 2010;17(5):530-8). PA has two domains, PA_(N) (a ˜25 kDa N-terminal domain;residues 1-197) and PA_(C) (˜55 kDa C-terminal domain; residues239-716). Crystal structures of PA_(C) have been determined in complexeswith N-terminal fragments of PB1 (He et al., Nature. 2008;454(7208):1123-6).

The RdRP of influenza A is responsible for the replication andtranscription of the viral RNA genes. The viral mRNA transcriptioninvolves a cap-snatching mechanism in which the polymerase binds tocellular mRNA via the 5′-cap and cleaves the mRNA 12-13 nucleotidesdownstream. The cleaved RNA fragment containing the 5′ cap acts as aprimer for viral mRNA synthesis (Plotch et al., Cell. 1981;23(2):847-58). Cap-snatching is an important event in the life cycle ofall members of Orthomyxoviridae family including influenza A, B and Cviruses, and the host cell has no analogous activity. Therefore,inhibitors of cap-snatching would act against all influenza subtypes andstrains, including tamiflu-resistant influenza A viruses, and will notinterfere with host cell activities.

The complete structure of the viral polymerase has not yet beendetermined at atomic resolution; however, recent structural studies ofparts of the influenza A polymerase (reviewed by Das et al., Nat StructMol Biol. 2010; 17(5):530-8) have begun to elucidate the architecture ofthis complex and started to identify multiple promising target sites fordesigning new influenza drugs. The crystal structures of the N-terminaldomain of PA subunit (PA_(N)) from H5N1 (Yuan et al., Nature. 2009;458(7240):909-13) and H3N2 (Dias et al., Nature. 2009; 458(7240):914-8)viruses established that the PA_(N) domain contains the endonucleaseactive site composed of conserved acidic residues E80, D108, and E119positioned in a deep cleft. Blocking the binding of host mRNAs to thecleft and/or inhibiting the cleavage of the host mRNAs would inhibit thesynthesis of the viral mRNAs and thereby, inhibit replication ofinfluenzaA.

The PA_(N) domain of 2009 pandemic H1N1 virus polymerase (residues1-204) has now been crystallized in three distinct forms (U.S. patentapplication Ser. No. 13/554,709). These new crystal forms provide forthe determination of 3-dimensional structures of PA_(N) withendonuclease inhibitors. In addition, a high-throughput methodology(U.S. patent application Ser. No. 13/554,709) has been developed andoptimized for screening of compounds for influenza endonucleaseinhibition.

Compounds, which inhibit influenza endonuclease, may have inhibitoryeffects on other drug targets owing to the conserved geometry of thecatalytic metals in nucleases and polynucleotidyl transferases. Indeed,early influenza endonuclease inhibitors were developed into an anti-AIDSdrug targeting HIV-1 integrase (Summa et al., J Med Chem. 2008;51(18):5843-55). Other viral drug targets with similar geometry at theircatalytic cores include, but are not limited to: NS5b RNA-dependent RNApolymerase of hepatitis C virus (Summa et al., J Med Chem. 2008;51(18):5843-55), RNase H of HIV-1 reverse transcriptase (Himmel et al.,Structure. 2009; 17(12): 1625-35), herpes virus terminase (Nadal et al.,Proc Natl Acad Sci USA. 2010; 107(37):16078-83), and SARS coronavirusNTPase/helicase. Two metal chelating compounds have also been found tohave antibacterial effects (Drakulić et al., ChemMedChem. 2009;4(12):1971-75) and antibacterial prenyl transferases specifically (Zhanget al., ACS Med Chem Lett. 2012; 3(5):402-6). In addition to antiviraland antibacterial effects, two metal chelating agents can have cytotoxiceffects on eukaryotic cells. One set of compounds was found to haveselective anti-leukemic cytotoxicity by inhibiting a terminaldeoxyribonucleotidyl transferase (Locatelli et al., Mol Pharm. 2005;68(2):538-50). In addition, it has been suggested that administration ofD-serine with a D-amino acid oxidase (DAAO) inhibitor could allow formore effective delivery of D-serine to the brain, which could beeffective in the treatment of symptoms of schizophrenia. Severalcompounds related to 3-hydroxypyridin(1H)2-ones and its aza-analogs haverecently been reported to have activity as D-amino acid oxidaseinhibitors (Hondo, et al., J. Med. Chem. 2012, 56, 3582-3592; Duplantieret al, J. Med. Chem., 2009, 52, 3576-3585).

SUMMARY OF THE INVENTION

Accordingly the invention provides a compound of formula I:

wherein:

X¹ is CR₅ and X² is CR₆; or X¹ is N and X² is CR₆; or X¹ is CR₅ and X²is N;

R₄ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b),—N(R^(y))S(O)_(n)R^(c), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₄ is optionally substituted with one ormore groups independently selected from R_(n);

R₅ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₅ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₅ is optionally substituted with one ormore groups independently selected from R_(n);

R₆ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₆ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle and heteroaryl of R₆ is optionally substituted with one ormore groups independently selected from R_(n);

each R^(a) and R^(b) is independently selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(a) and R^(b) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(a) and R^(b) is optionallysubstituted with one or more groups independently selected from R_(n);

each R^(c) is independently selected from hydrogen, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(c) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(c) is optionally substitutedwith one or more groups independently selected from R_(n);

each R^(e) and R^(f) is independently selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl; and

each R^(g) is independently selected from hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl;

each R_(m) is independently selected from cyano, halo, nitro, hydroxy,oxo, carboxy, aryl, heteroaryl, heterocycle, aryloxy, heteroaryloxy,heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g),—S(O)_(n)NR^(e)R^(f), —COOR^(g), and —CONR^(e)R^(f); wherein eachheterocycle of R_(m) is optionally substituted with one or more groupsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, cyano, halo, nitro,hydroxy, oxo, carboxy, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g), and—CONR^(e)R^(f); and wherein each aryl and heteroaryl of R_(m) isoptionally substituted with one or more groups independently selectedfrom (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, cyano, halo, nitro, hydroxy, carboxy, R_(m1),aryloxy, heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, —COOR^(g),and —CONR^(e)R^(f);

each R_(m1) is independently selected from aryl and heteroaryl, whereinany aryl and heteroaryl of R_(m1) is optionally substituted with one ormore groups independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, heterocycle, aryl,heteroaryl, cyano, halo, nitro, hydroxy, carboxy, —NR^(e)R^(f),—S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f),(C₁-C₆)alkoxy, —COOR^(g), and —CONR^(e)R^(f);

each R_(n) is independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, heterocycle, and (C₃-C₁₂)carbocycle ofR_(n) is optionally substituted with one or more groups independentlyselected from cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); wherein each aryland heteroaryl of R_(n) is optionally substituted with one or moregroups independently selected from cyano, halo, nitro, hydroxy, oxo,carboxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, and —CONR^(e)R^(f);

each R^(y) is independently selected from hydrogen and (C₁-C₆)alkyl; and

n is 0, 1, or 2;

or a salt or prodrug thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable excipient.

The invention also provides a method to promote an antiviral effect inan animal (e.g., a human) comprising administering a compound of formulaI, or a pharmaceutically salt thereof, to the animal.

The invention also provides a method to inhibit an endonuclease in ananimal (e.g., a human) in need of such treatment comprisingadministering a compound of formula I, or a pharmaceutically saltthereof, to the animal.

The invention also provides a method to inhibit an exonuclease in ananimal (e.g., a human) in need of such treatment comprisingadministering a compound of formula I, or a pharmaceutically saltthereof, to the animal.

The invention also provides a method to treat influenza in an animal(e.g., a human) comprising administering a compound of formula I, or apharmaceutically salt thereof, to the animal.

The invention also provides a method to treat HIV in an animal (e.g., ahuman) comprising administering a compound of formula I, to the animal.

The invention also provides a method to inhibit DAAO in an animalcomprising administering a compound of formula I to the animal.

The invention also provides a method to treat schizophrenia in an animalcomprising administering a compound of formula I and D-serine to theanimal.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for use in medical therapy.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic or therapeutictreatment of a viral infection.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic inhibition of anendonuclease.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic inhibition of anexonuclease.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic or therapeutictreatment of influenza.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic or therapeutictreatment of HIV.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic or therapeutictreatment of a disease or condition associated with DAAO activity.

The invention also provides a compound of formula I, or apharmaceutically salt thereof for the prophylactic or therapeutictreatment of schizophrenia when administered with D-serine

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for treating aviral infection in an animal (e.g., a human).

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for inhibiting anendonuclease in an animal (e.g., a human).

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for inhibiting anexonuclease in an animal (e.g., a human).

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for treatinginfluenza in an animal (e.g., a human).

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for treating HIVin an animal (e.g., a human).

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for treating adisease or condition associated with DAAO activity.

The invention also provides the use of a compound of formula I, or apharmaceutically salt thereof to prepare a medicament for treatingschizophrenia (e.g. when administered with D-serine).

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing a compound of formula I or a salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates data generated from Example 63.

FIG. 2 illustrates 3D SAR for representative pyridinone compounds fromExample 61. Metal coordinating and hydrogen bonds are depicted as blackdashes, hydrophobic and cation-π interactions are grey. Residues withsignificant structural changes upon binding of a ligand are shown withthe apo structure colored light grey.

FIG. 3 illustrates the crystal structure of 5-bromopyridine-2,3-diolbound to the RNase H active site of HIV-1 from Example 65.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as propyl embraces only the straight chain radical, abranched chain isomer such as isopropyl being specifically referred to.Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic. Heteroaryl encompasses a radical of a monocyclic aromaticring containing five or six ring atoms consisting of carbon and one tofour heteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(X) wherein X is absent or is H, O, (C₁-C₄)alkyl,phenyl or benzyl, as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms comprising one to fourheteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(X).

The term “heterocycle” as used herein refers to a single saturated orpartially unsaturated ring or a multiple condensed ring system. The termincludes single saturated or partially unsaturated rings (e.g. 3, 4, 5,6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1to 3 heteroatoms selected from the group consisting of oxygen, nitrogenand sulfur in the ring. The ring may be substituted with one or more(e.g. 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may alsobe present in their oxidized forms. Such rings include but are notlimited to azetidinyl, tetrahydrofuranyl or piperidinyl. The term“heterocycle” also includes multiple condensed ring systems (e.g. ringsystems comprising 2, 3 or 4 rings) wherein a single heterocycle ring(as defined above) can be condensed with one or more heterocycles (e.g.decahydronapthyridinyl), carbocycles (e.g. decahydroquinolyl) or aryls.The rings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the point of attachment of amultiple condensed ring system (as defined above for a heterocycle) canbe at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g. a nitrogen). Exemplary heterocyclesinclude, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and 1,4-benzodioxanyl.

The term “(C₃-C₁₂)carbocycle” refers to a single saturated (i.e.,cycloalkyl) or a single partially unsaturated (e.g., cycloalkenyl,cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms (i.e.(C₃-C₇)carbocycle). The term “carbocycle” or “carbocyclyl” also includesmultiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g. bicyclic carbocycleshaving about 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 carbon atoms). The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Forexample, multicyclic carbocyles can be connected to each other via asingle carbon atom to form a spiro connection (e.g. spiropentane,spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fusedconnection (e.g. carbocycles such as decahydronaphthalene, norsabinane,norcarane) or via two non-adjacent carbon atoms to form a bridgedconnection (e.g. norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” can also be optionally substituted withone or more (e.g. 1, 2 or 3) oxo groups. Non-limiting examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

The term “prodrug” as used herein refers to a compound that whenadministered to a biological system (e.g. a mammal such as a human)generates the drug substance, i.e. active ingredient, as a result ofspontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s),photolysis, and/or metabolic chemical reaction(s) or by some otherprocess. A prodrug is thus a modified (e.g. covalently modified) analogor latent form of a therapeutically-active compound. A prodrug may alsobe an active metabolite or therapeutically-active compound itself. Byway of example a prodrug may generate the active inhibitory compoundduring metabolism, systemically, inside a cell, by hydrolysis, enzymaticcleavage, or by some other process (Bundgaard, Hans, “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development(1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood AcademicPublishers, pp. 113-191; Tranoyl-Opalinski, I., Fernandes, A., Thomas,M., Gesson, J.-P., and Papot, S., Anti-Cancer Agents in Med. Chem., 8(2008) 618-637). Enzymes which are capable of an enzymatic activationmechanism with the prodrug compounds of the invention include, but arenot limited to nitroreductase, proteases (e.g. serine proteases such asprostate specific antigen (PSA), amidases, esterases, microbial enzymes,phospholipases, cholinesterases, and phosphases).

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase.

When a bond is drawn in a non-stereochemical manner (e.g. flat) the atomto which the bond is attached includes all stereochemical possibilities.It is also to be understood that when a bond is drawn in astereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)the atom to which the stereochemical bond is attached has thestereochemistry as shown unless otherwise noted.

Accordingly, in one embodiment, a compound of the invention may begreater than 50% a single enantiomer. In another embodiment, a compoundof the invention may be at least 51% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 60% a singleenantiomer. In another embodiment, a compound of the invention may be atleast 70% a single enantiomer. In another embodiment, a compound of theinvention may be at least 80% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 90% a singleenantiomer. In another embodiment, a compound of the invention may be atleast 95% a single enantiomer. In another embodiment, a compound of theinvention may be at least 98% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 99% a singleenantiomer. In another embodiment, a compound of the invention may begreater than 50% a single diastereomer. In another embodiment, acompound of the invention may be at least 51% a single diastereomer. Inanother embodiment, a compound of the invention may be at least 60% asingle diastereomer. In another embodiment, a compound of the inventionmay be at least 70% a single diastereomer. In another embodiment, acompound of the invention may be at least 80% a single diastereomer. Inanother embodiment, a compound of the invention may be at least 90% asingle diastereomer. In another embodiment, the compounds of theinvention are at least 95% a single diastereomer. In another embodiment,a compound of the invention may be at least 98% a single diastereomer.In another embodiment, a compound of the invention may be at least 99% asingle diastereomer.

It will be appreciated by those skilled in the art that compounds offormula I can also exist in various tautomeric forms (illustratedbelow).

It is to be understood that the present invention encompasses alltautomeric forms of a compound of formula I as well as mixtures thereof,which possess the useful properties described herein.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. Thespecific listed below are values for compounds of formula I and allsubformulas of formula I (e.g., compounds of formulas Ia, Ib and Ic). Itis understood that two or more specific values may be combined together.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;(C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;(C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy,butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can bephenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

A specific group of compounds are compounds of formula Ia:

or salts thereof.

A specific group of compounds are compounds of formula Ib:

or salts thereof.

A specific group of compounds are compounds of formula Ic:

or salts thereof.

A specific group of compounds are compounds wherein X¹ is CR₅ and X² isCR₆.

A specific group of compounds are compounds wherein X¹ is N and X² isCR₆; or X¹ is CR₅ and X² is N.

A specific group of compounds I are compounds wherein X¹ is N and X² isCR₆.

A specific group of compounds are compounds wherein X¹ is CR₅ and X² isN.

A specific value for R₄ is H, fluoro, chloro, trifluoromethyl, ormethyl.

A specific value for R₄ is H.

A specific value for R₄ is fluoro.

A specific value for R₄ is H, fluoro, chloro, trifluoromethyl, methyl oraryl, wherein any aryl of R₄ is optionally substituted with one or moregroups independently selected from R_(n).

A specific value for R_(n) is halo.

A specific value for R₄ is H, fluoro, chloro, trifluoromethyl, methyl orphenyl, wherein phenyl is optionally substituted with one or more halo.

A specific value for R₄ is H or phenyl, wherein phenyl is optionallysubstituted with one or more halo.

A specific value for R₄ is H or 4-fluorophenyl.

A specific value for R₄ is methyl.

A specific value for R₅ is H, halo, (C₁-C₆)alkyl, (C₃-C₁₂)carbocycle,—NR^(a)R^(b), or aryl, wherein each (C₁-C₆)alkyl and (C₃-C₁₂)carbocycleis optionally substituted with one or more groups independently selectedfrom R_(m); and wherein any aryl is optionally substituted with one ormore groups independently selected from R_(n).

A specific value for R₅ is H, halo or aryl, wherein any aryl of R₅ isoptionally substituted with one or more groups independently selectedfrom R_(n).

A specific value for R₅ is H, halo or phenyl, wherein phenyl isoptionally substituted with one or more groups independently selectedfrom R_(n).

A specific value for R_(n) is independently selected from heteroaryl,halo, nitro, and —CONR^(e)R^(f); wherein each aryl and heteroaryl ofR_(n) is optionally substituted with one or more groups independentlyselected from cyano, halo, nitro, hydroxy, oxo, carboxy, aryl,heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy, —NR^(e)R^(f),—S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g), —S(O)_(n)NR^(e)R^(f),(C₁-C₆)alkoxy, and —CONR^(e)R^(f).

A specific value for each R_(n) is independently selected fromheteroaryl, cyano, halo, nitro, and —CONR^(e)R^(f).

A specific value for R₅ is H, methyl, 4-tetrazol-5-ylphenyl, cyclohexyl,3-tetrazol-5-ylphenyl, 3-carboxyphenyl, 4-carboxyphenyl,4-cyanophenylamino, 3-cyanophenyl, 3-carboxyphenyl, benzyl,3-fluorophenyl, bromo, phenyl, 4-fluorophenyl, 3-aminocarbonylphenyl,4-aminocarbonylphenyl, 4-nitrophenyl, or 4-cyanophenyl.

A specific value for R₅ is H, 3-fluorophenyl, bromo, phenyl,4-fluorophenyl, 3-aminocarbonylphenyl, 4-aminocarbonylphenyl, or4-nitrophenyl 4-cyanophenyl or 4-tetrazol-2-ylphenyl

A specific value for R₅ is H, methyl, 3-fluorophenyl, bromo, phenyl,4-fluorophenyl, 3-aminocarbonylphenyl, 4-aminocarbonylphenyl, or4-nitrophenyl.

A specific value for R₅ is phenyl, benzyl, 2-pyridyl, 3-pyridyl, or4-pyridyl wherein the phenyl or pyridyl is optionally substituted withone or more groups selected from the group consisting of —COOH,—CONR^(e)R^(f), —SO₃H, —SO₂NHCH₃, OH, OCH₃, F, Cl, Br, CH₃; or whereinR₅ is methyl substituted with COOH, SO₃H, SO₂NHCH₃, OH, a CF₃ or atetrazole.

A specific value for RP is H, halo, (C₁-C₆)alkyl, (C₃-C₁₂)carbocycle oraryl, wherein each (C₁-C₆)alkyl and (C₃-C₁₂)carbocycle is optionallysubstituted with one or more groups independently selected from R_(m);and wherein any aryl is optionally substituted with one or more groupsindependently selected from R_(n).

A specific value for R₆ is H, halo, (C₃-C₁₂)carbocycle or aryl, whereinany aryl of R₆ is optionally substituted with one or more groupsindependently selected from R_(n).

A specific value for R₆ is H, halo, cyclohexyl, cyclohexenyl, or phenyl,wherein any cyclohexyl, cyclohexenyl, or phenyl of R₆ is optionallysubstituted with one or more groups independently selected from R_(n).

A specific value for each R_(n) is independently selected from(C₁-C₆)alkyl (C₁-C₆)alkoxy, heteroaryl, cyano, halo, nitro, hydroxy, and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl and (C₁-C₆)alkoxy of R_(n) isoptionally substituted with one or more groups independently selectedfrom cyano, halo, nitro, hydroxy, carboxy, aryloxy, heteroaryloxy,heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g),—COOR^(g), and —CONR^(e)R^(f); wherein each heteroaryl of R_(n) isoptionally substituted with one or more groups independently selectedfrom cyano, halo, nitro, hydroxy, oxo, carboxy, aryl, heteroaryl,aryloxy, heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), —S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy,and —CONR^(e)R^(f).

A specific value for each R_(n) is independently selected from(C₁-C₆)alkyl (C₁-C₆)alkoxy, heteroaryl, cyano, halo, nitro, hydroxy, and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl of R_(n) is optionallysubstituted with one or more halo.

A specific value for R₆ is H, bromo, phenyl, 4-tert-butylphenyl,4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl,3-methoxyphenyl, 3-fluorophenyl, cyclohex-1-en-1-yl, cyclohexyl,3,4-dihydroxyphenyl, 4-nitrophenyl, 3-aminocarbonylphenyl,4-aminocarbonylphenyl, 4-cyanophenyl, 3-cyanophenyl,3-tetrazol-5-ylphenyl, 3-carboxyphenyl, 4-phenylbenzyl, or4-tetrazol-5-ylphenyl.

A specific value for R₆ is H, bromo, phenyl, 4-tert-butylphenyl,4-trifluoromethylphenyl, 4-fluorophenyl, 4-methoxyphenyl,3-methoxyphenyl, 3-fluorophenyl, cyclohex-1-en-1-yl, cyclohexyl,3,4-dihydroxyphenyl, 4-nitrophenyl, 3-aminocarbonylphenyl,4-aminocarbonylphenyl, 4-cyanophenyl, 3-cyanophenyl,3-tetrazol-2-ylphenyl or 4-tetrazol-2-ylphenyl.

A specific value for R₆ is H, bromo, phenyl, 4-tert-butylphenyl,4-trifluoromethylphenyl, 4-fluorophenyl, 3-methoxyphenyl,3-fluorophenyl, cyclohex-1-en-1-yl, 3,4-dihydroxyphenyl,4-cyclohexylphenyl, 4-nitrophenyl, 3-aminocarbonylphenyl, or4-aminocarbonylphenyl.

A specific value for R₆ is phenyl or benzyl, which phenyl or benzyl isoptionally substituted with one or more substituents selected from thegroup consisting of F, Cl, Br, OCH₃, CH₃, and CONR^(e)R^(f).

A specific compound is a compound wherein:

R₄ is H;

R₅ is H, halo or aryl wherein each aryl of R₅ is optionally substitutedwith one or more groups independently selected from R_(n); and

R₆ is (C₃-C₁₂)carbocycle or aryl, wherein each (C₃-C₁₂)carbocycle of R₆is optionally substituted with one or more groups independently selectedfrom R_(m); and wherein each aryl of R₆ is optionally substituted withone or more groups independently selected from R_(n).

A specific compound is a compound wherein:

R₄ is H;

R₅ is H, halo or phenyl wherein each phenyl of R₅ is optionallysubstituted with one or more groups independently selected from R_(n);and

R₆ is (C₆)carbocycle or phenyl, wherein each (C₆)carbocycle of R₆ isoptionally substituted with one or more groups independently selectedfrom R_(m); and wherein each phenyl of R₆ is optionally substituted withone or more groups independently selected from R_(n).

A specific compound is a compound wherein:

R₅ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl andheteroaryl, of R₄ is optionally substituted with one or more groupsindependently selected from R_(n); and

R₆ is bromo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl, heterocycle,—NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₂-C₆)alkoxy, and(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl andheteroaryl, of R₄ is optionally substituted with one or more groupsindependently selected from R_(n).

A specific compound is a compound wherein:

R₅ is (C₁-C₃)alkyl, aryl, heteroaryl, wherein each (C₁-C₃)alkyl of R₅ isoptionally substituted with one or more groups independently selectedfrom R_(m); and wherein each aryl and heteroaryl of R₅ is optionallysubstituted with one or more groups independently selected from R_(n);and

R₆ is bromo, (C₁-C₃)alkyl, (C₃-C₈)carbocycle, aryl, heteroaryl, whereineach (C₁-C₆)alkyl, (C₃-C₁₂)carbocycle of R₆ is optionally substitutedwith one or more groups independently selected from R_(m); and whereineach aryl and heteroaryl, of R₆ is optionally substituted with one ormore groups independently selected from R_(n).

A specific compound is:

or a pharmaceutically acceptable salt thereof.

A specific compound is:

or a pharmaceutically acceptable salt thereof.

A specific group of compounds are compounds of formula Ia:

wherein:

R₄ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b),—N(R^(y))S(O)_(n)R^(c), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₄ is optionally substituted with one ormore groups independently selected from R_(n);

R₅ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₅ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₅ is optionally substituted with one ormore groups independently selected from R_(n);

R₆ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₆ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₆ is optionally substituted with one ormore groups independently selected from R_(n);

each R^(a) and R^(b) is independently selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(a) and R^(b) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(a) and R^(b) is optionallysubstituted with one or more groups independently selected from R_(n);

each R^(c) is independently selected from hydrogen, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(c) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(c) is optionally substitutedwith one or more groups independently selected from R_(n);

each R^(e) and R^(f) is independently selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl; and

each R^(g) is independently selected from hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl;

each R_(m) is independently selected from cyano, halo, nitro, hydroxy,oxo, carboxy, aryl, heteroaryl, heterocycle, aryloxy, heteroaryloxy,heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g),—S(O)_(n)NR^(e)R^(f), —COOR^(g), and —CONR^(e)R^(f); wherein eachheterocycle of R_(m) is optionally substituted with one or more groupsindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, cyano, halo, nitro,hydroxy, oxo, carboxy, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g), and—CONR^(e)R^(f); wherein each aryl and heteroaryl of R_(m) is optionallysubstituted with one or more groups independently selected from cyano,halo, nitro, hydroxy, carboxy, aryl, heteroaryl, aryloxy, heteroaryloxy,heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, —COOR^(g), and —CONR^(e)R^(f);

each R_(n) is independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, heterocycle, and (C₃-C₁₂)carbocycle ofR_(n) is optionally substituted with one or more groups independentlyselected from cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); wherein each aryland heteroaryl of R_(n) is optionally substituted with one or moregroups independently selected from cyano, halo, nitro, hydroxy, oxo,carboxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, and —CONR^(e)R^(f);

each R^(y) is independently selected from hydrogen and (C₁-C₆)alkyl; and

n is 0, 1, or 2;

or a salt thereof.

In one embodiment the compound of formula I is not5-chloro-3-hydroxypyridin-2(1H)-one, 5-bromo-3-hydroxypyridin-2(1H)-one,or 3-hydroxy-5-methylpyridin-2(1H)-one.

In one embodiment the compound of formula I is not a compound of thefollowing formula:

wherein R₅ is bromo, phenethyl, hydrogen, chloro, or methyl.

In one embodiment the compound of formula I is not a compound of thefollowing formula:

wherein R₅ is phenethyl, alpha-methylbenzyl, 3-phenylpropyl,4-chlorophenethyl, 2-(4-chlorophenyl)ethenyl, 3,3-dimethylbytyl,phenoxymethyl, 2-fluorophenethyl, 3-fluorophenethyl, 3-methoxyphenethyl,4-fluorophenethyl, 4-methoxyphenethyl, 3,5-difluorophenethyl, or3,5-dimethoxyphenethyl.

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated in the followingSchemes wherein the meanings of the generic radicals are as given aboveunless otherwise qualified.

The above scheme can also be used to prepare compounds of formula Iwherein the group NR_(e)R_(f) is replaced with an N-linked heterocycle.

In Schemes 7a and 7b, the groups R_(n1) and R_(n2) are eachindependently selected from the values for Rn described herein.

In cases where compounds are sufficiently basic or acidic, a salt of acompound of formula I can be useful as an intermediate for isolating orpurifying a compound of formula I. Additionally, administration of acompound of formula I as a pharmaceutically acceptable acid or base saltmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to an avian or a mammalian host, such as ahuman patient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

The compounds can also be administered by inhalation, for example, byoral or nasal inhalation and can be formulated accordingly.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The compounds of the invention are useful for inhibiting endonucleasesas well as for inhibiting exonucleases and polynucleotidyl transferases.Thus, the compounds of the invention are useful for treating conditionsassociated with endonuclease or exonucleases activity, and inparticular, conditions wherein inhibition of endonuclease orexonucleases activity is indicated. Additionally, in one embodiment, theinvention provides a method to treat a viral infection. Viral infectionstreatable with compounds of the invention include viruses of theOrthomyxoviridae family (e.g. influenza A, influenza B and influenza C),and viruses of the Arenaviridae and Bunyaviridae families of viruses(e.g. Hantavirus). In one specific embodiment the compounds of theinvention are useful for treating viruses associated with “influenza Acap snatching endonucleases.” In another specific embodiment thecompounds of the invention are useful as anti-HIV integrase and RNase Hagents; thus, they are also useful for treating pathological conditionsassociated with such enzymes.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 Preparation of Compound

To a solution of 5-methyl-2-ethoxy-3-methoxypyridine (110 mg, 0.72 mmol)stirred in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide(1M solution in CH₂Cl₂) (1.0 ml). After addition was completed, thereaction mixture was stirred for 16 hours at room temperature.Dichloromethane was removed under vacuum and aq.HCl (3N) was added. Theresulting solid was filtered and then redissolved in CH₂Cl₂ and washedwith NaHCO₃ and brine, dried and evaporated under reduced pressure toafford a tan solid (65 mg (72% yield). ¹H NMR (300 MHz, MeOD-d₄) δ:6.75(s, 1H), 6.7 (s, 1H), 1.99 (s, 3H).

The intermediates were prepared as follows.

a. Preparation of Compound

A solution of 3-(methoxy)-5-bromopyridine (2.0 g, 10.6 mmol.) andmeta-chloroperbenzoic acid (mCPBA; 2.5 g, 14.8 mmol) in dichloromethane(50 ml) was stirred at room temperature for 3 hours. The reactionmixture was washed with 15 mL 2N KOH followed by brine. The organiclayers were dried over anhydrous MgSO₄ and concentrated in vacuo to giveproduct as white solid (1.06 g, 51%).

b. Preparation of Compound

Phosphoryl chloride (POCl₃) (4.8 mL, 52.9 mmol) was added to a solutionof 5-bromo-3-methoxy-pyridine oxide (540 mg, 2.6 mmol) in 15 ml CH₂Cl₂.The reaction mixture was stirred at room temperature overnight. Thereaction mixture was washed with sat. sodium bicarbonate and brine. Theorganic layer was dried, concentrated and purified using ISCO flashchromatography using 50% ethyl acetate in hexane to provide 369 mgproduct (62% yield). ¹H NMR (300 MHz, CDCl₃) δ: 8.05 (s, 1H), 7.34 (s,1H), 3.93 (s, 3H).

c. Preparation of Compound

To a 25 mL flask containing (63.8 mg, 1.2 mmol) of sodium ethoxide wasadded 3 mL dry ethanol. The mixture was stirred for 30 minutes.2-Chloro-3-methoxy-5-bromopyridine (230 mg, 1.04 mmol) was added to themixture and heated to 60° C. for 16 hours. The reaction was allowed tocool and the solvent was removed. Ethyl acetate was added (50 ml) wasadded to the residue. The ethyl acetate solution was washed with waterand then brine. The organic solvent was dried and concentrated, purifiedby ISCO flash chromatography using 10% ethyl acetate in hexane to give220 mg (97% yield) of the desired product. ¹H NMR (300 MHz, CDCl₃) δ:7.71 (s, 1H), 7.09 (s, 1H), 4.37 (qt, 2H), 3.82 (s, 3H), 1.38 (t, 3H).

d. Preparation of Compound

To a solution of known 2-ethoxy-3-methoxy-5-bromopyridine (100 mg, 0.34mmol) in 1,4-dioxane (3.0 ml), trimethyl boroxine (80 mg, 0.69 mmol) andPd(dppf)Cl₂ (56.3 mg, 0.069 mmol) was added, followed by CsCO₃ (300 mg,0.92 mmol). The mixture was degassed for 30 minutes, and then heated to90° C. for 16 hr. After cooling, the crude mixture was filtered oncelite and extracted with EtOAc (3×), washed with NaCl, the organiclayer was dried with Na₂SO₄ and concentrated to give crude product. Thecrude product was purified by ISCO flash chromatography using 10% EtOAcin hexane, giving 50 mg compound (Yield: 84%). ¹H NMR (300 MHz, CDCl₃)δ: 7.52 (s, 1H), 6.84 (s, 1H), 4.45 (q, 2H), 3.82 (s, 3H), 2.21 (s, 3H),1.39 (t, 3H).

Example 2 Preparation of Compound

To a solution of 2,3-(dibenzyloxy)-6-(4-fluorophenyl)pyridine (50 mg,0.129 mmol) in MeOH (10 ml), palladium 10 wt % on activated carbon(catalytic amount) was added. This mixture was then stirred underhydrogen using balloon for 16 hours. The mixture was then filteredthrough Celite and was washed with MeOH (15 ml). The solvent was thenevaporated under reduced pressure to afford a tan solid 15 mg (yield:57%). ¹H NMR (300 MHz, MeOD-d₄) δ: 7.65-7.60 (m, 2H), 7.21 (t, J=9.0 Hz,2H), 6.95 (d, J=6.0 Hz, 1H), 6.47 (d, J=6.0 Hz, 1H).

The intermediates were prepared as follows:

a. Preparation of Compound

To a suspension of 2-bromopyridin-3-ol (2.41 g, 13.9 mmol) in 34.6 mLwater was added potassium carbonate (3.83 g, 27.7 mmol), then iodine(3.87 g, 15.2 mmol), and this mixture was stirred at room temperaturefor 12 hours. The reaction mixture was then cooled to 0° C., 2N aq HClwas added until pH 6. The resulting precipitate was collected byfiltration, washed with water and dried to give2-bromo-6-iodopyridine-3-ol (3.6 g, 83% yield). LC/MS: 300 (M+H); ¹H NMR(300 MHz, CDCl₃) δ: 7.45 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H).

b. Preparation of Compound

To a solution of 2-bromo-6-iodopyridine-3-ol (1.0 g, 3.33 mmol) in 10 mLmethanol was added potassium carbonate (922 mg, 6.67 mmol) and benzylbromide (1.19 mL, 10.0 mmol), and the resulting mixture was heated at50° C. for 12 hours. After cooling to room temperature, the solvent wasremoved and the resulting residue was partitioned between water andethyl acetate. The organic layer was dried and evaporated to give thecrude product, which was pure enough for the next step. ¹H NMR (300 MHz,CDCl₃) δ: 7.49 (d, J=8.4 Hz, 1H), 7.39-7.33 (m, 5H), 6.82 (d, J=8.4 Hz,1H), 5.13 (s, 2H).

c. Preparation of Compound

To a solution of benzyl alcohol (1.3 g) in 4 mL DMF was slowly added NaH(400 mg) at 0° C. The mixture was stirred at room temperature for 30minutes after which 3-(benzyloxy)-2-bromo-6-iodopyridine (1.2 g) wasadded. The resulting solution was heated to 100° C. for 1 hour undernitrogen. After cooling, the mixture was diluted with water andextracted with ethyl acetate. The organic layer was dried, evaporatedunder vacuum and purified ISCO flash chromatography to give the desiredproduct in 85% yield. ¹H NMR (300 MHz, CDCl₃) δ: 7.50-7.22 (m, 10H),7.13 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.44 (s, 2H), 5.1 (s,2H).

d. Preparation of Compound

To a solution of 6-iodo-2,3-dibenzyloxypyridine (60 mg, 0.14 mmol) in 4ml dioxane:water (3:1) was added 4-fluorophenylboronic acid (40 mg, 0.28mmol) and potassium carbonate (39 mg, 0.28 mmol). The resulting mixturewas degassed for 15 minutes after which Pd (PPh₃)₄ (16 mg, 0.014 mmol)was added and the mixture was further degassed for 15 minutes. Thereaction mixture was then heated at 100° C. for 12 hours. After coolingto room temperature, the reaction mixture was diluted with ethyl acetateand was washed with saturated sodium bicarbonate, followed by brine. Theorganic phase was dried with sodium sulfate and concentrated underreduced pressure to afford crude product which was purified by ISCOflash chromatography using 10%-100% EtOAc in hexane to afford pureproduct 50 mg solid (90%). ¹H NMR (300 MHz, CDCl₃) δ: 7.88-7.85 (m, 2H),7.55-7.53 (m, 2H), 7.41-7.32 (m, 8H), 7.15-7.06 (m, 4H), 5.61 (s, 2H),5.19 (s, 2H).

Example 3 Preparation of Compound

To a solution of 2,3-(dibenzyloxy)-6-(4-t-butylphenyl)pyridine (25 mg,0.06 mmol) in MeOH (10.0 ml), palladium (10 wt % on activated carbon,catalytic amount) was added. This mixture was then stirred underhydrogen using balloon for 16 hours. The mixture was then filteredthrough Celite and was washed with MeOH (15 ml). The solvent was thenevaporated under reduced pressure to afford a tan solid 10 mg (yield:70%). ¹H NMR (300 MHz, MeOD-d₄) δ: 7.42 (m, 4H), 6.82 (d, J=6.0 Hz, 1H),6.4 (d, J=6.0 Hz, 1H), 1.26 (s, 9H).

The intermediate was prepared as follows.

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (60mg, 0.14 mmol) in 4 ml dioxane:water (3:1) was added4-t-butylphenylboronic acid (40 mg, 0.28 mmol) and potassium carbonate(39 mg, 0.28 mmol). The resulting mixture was degassed for 15 minutesafter which Pd (PPh₃)₄ (16 mg, 0.014 mmol) was added and the mixture wasfurther degassed for 15 minutes. The reaction mixture was then heated at100° C. for 12 hours. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate and was washed with saturatedsodium bicarbonate, followed by brine. The organic phase was dried withsodium sulfate and concentrated under reduced pressure to afford crudeproduct which was purified by ISCO flash chromatography using 10%-100%EtOAc in hexane to afford 44 mg product pure product (yield: 72%) ¹H NMR(300 MHz, CDCl₃) δ: 7.85 (d, J=8.7 Hz, 2H), 7.54 (d, J=6.9 Hz, 2H),7.45-7.3 (m, 10H), 7.20 (d, J=8.0 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 5.63(s, 2H), 5.17 (s, 2H), 1.35 (s, 9H).

Example 4 Preparation of Compound

To a solution of 2,3-(dibenzyloxy)-6-[(4-CF₃)phenyl)]pyridine (25 mg,0.057 mmol) in MeOH (10.0 ml), Palladium (10 wt % on activated carbon,catalytic amount) was added. This mixture was then stirred underhydrogen using balloon for 16 hours. The mixture was filtered throughCelite and washed with MeOH (15 ml). The solvent was then evaporatedunder reduced pressure to afford a tan solid 10 mg (yield: 69%): ¹H NMR(300 MHz, MeOD-d₄) δ: 7.72 (m, 4H), 7.0 (d, J=6.0 Hz, 1H), 6.48 (d,J=6.0 Hz, 1H).

The intermediate was prepared as follows.

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (50mg, 0.12 mmol) in 4 ml dioxane:water (3:1) was added4-(trifluoromethyl)phenylboronic acid (45.5 mg, 0.24 mmol) and potassiumcarbonate (36 mg, 0.24 mmol). The resulting mixture was degassed for 15minutes after which Pd (PPh₃)₄ (14 mg, 0.012 mmol) was added and themixture was further degassed for 15 minutes. The reaction mixture wasthen heated at 100° C. for 12 hours. After cooling to room temperature,the reaction mixture was diluted with ethyl acetate and was washed withsaturated sodium bicarbonate, followed by brine. The organic phase wasdried with sodium sulfate and concentrated under reduced pressure toafford crude product which was purified by ISCO flash chromatographyusing 10%-100% EtOAc in hexane to afford 25 mg product pure product(yield: 48%); ¹H NMR (300 MHz, CDCl₃) δ: 7.99 (d, J=8.1 Hz, 2H), 7.64(d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.43-7.23 (m, 11H), 7.11 (d,J=8.1 Hz, 1H), 5.61 (s, 2H), 5.19 (s, 2H).

Example 5 Preparation of Compound

To a solution of 2,3-(dibenzyloxy)-6-(phenyl)pyridine (76 mg, 0.2 mmol)in MeOH (10 ml), Palladium 10 wt % on activated carbon (catalyticamount) was added. This mixture was then stirred under hydrogen usingballoon for 16 hours. The mixture was then filtered through Celite andwashed with MeOH (15 ml). The solvent was then evaporated under reducedpressure to afford a solid 25 mg (yield: 64%). ¹H NMR (300 MHz, MeOD-d₄)δ: 7.60-7.41 (m, 5H), 6.94 (d, J=7.5 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H).

The intermediate was prepared as follows.

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (100mg, 0.23 mmol) in (3:1) ml dioxane:water was added phenylboronic acid(58.2 mg, 0.47 mmol) and potassium carbonate (66 mg, 0.46 mmol). Theresulting mixture was degassed for 15 minutes after which Pd (PPh₃)₄ (35mg, 0.03 mmol) was added and the mixture was further degassed for 15minutes. The reaction mixture was then heated at 100° C. for 12 hours.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and was washed with saturated sodium bicarbonate, followedby brine. The organic phase was dried with sodium sulfate andconcentrated under reduced pressure to afford crude product which waspurified by ISCO flash chromatography using 10%-100% EtOAc in hexane toafford 76 mg product pure product (yield: 86%)¹H NMR (300 MHz, CDCl₃) δ:7.92 (d, J=7.2 Hz, 2H), 7.6 (d, J=7.2 Hz, 2H), 7.44-7.32 (m, 10H), 7.23(d, J=8.4 Hz, 2H), 7.13 (d, 1H), 5.64 (s, 2H), 5.19 (s, 2H).

Example 6 Preparation of Compound

To a solution of 2,3-(dibenzyloxy)-6-(4-methoxyphenyl)pyridine (100 mg,0.26 mmol) in MeOH (10 ml), Palladium 10 wt % on activated carbon(catalytic amount) was added. This mixture was then stirred underhydrogen using balloon for 16 hours. The mixture was then filteredthrough Celite and was washed with MeOH (15 ml). The solvent was thenevaporated under reduced pressure to afford a solid 14 mg (yield: 25%).¹H NMR (300 MHz, MeOD-d₄) δ: 7.5 (d, J=6.0 Hz, 2H), 7.12 (d, 1H), 6.82(d, 2H), 6.7 (d, J=6.0 Hz, 1H). 3.68 (s, 3H).

The intermediate was prepared as follows

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (100mg, 0.23 mmol) in 4 ml dioxane:water (3:1) added 4-methoxyphenylboronicacid (72.9 mg, 0.48 mmol) and potassium carbonate (66 mg, 0.48 mmol).The resulting mixture was degassed for 15 minutes after which Pd (PPh₃)₄(35 mg, 0.03 mmol) was added and the mixture was further degassed for 15minutes. The reaction mixture was then heated at 100° C. for 12 hours.After cooling to room temperature, the reaction mixture was diluted withethyl acetate and was washed with saturated sodium bicarbonate, followedby brine. The organic phase was dried with sodium sulfate andconcentrated under reduced pressure to afford crude product which waspurified by ISCO flash chromatography using 10%-100% EtOAc in hexane toafford 90 mg of the desired product (yield: 94%) ¹H NMR (300 MHz, CDCl₃)δ: 7.84 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 7.4-7.3 (m, 8H), 7.10(qt, J=7.8 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 5.60 (s, 2H), 5.16 (s, 2H),3.83 (s, 3H).

Example 7 Preparation of Compound

To a solution of 2,3-bis(benzyloxy)-6-(3-fluorophenyl)pyridine (100 mg,0.23 mmol) in MeOH (10.0 ml), palladium 10 wt % on activated carbon(catalytic amount) was added. This mixture was charged with hydrogenusing balloon and the reaction was run for 16 hours. The mixture wasfiltered on celite and was washed with MeOH (15.0 ml). The filtrate wasevaporated under reduced pressure to afford a solid (25 mg) in 50.1%yield. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.36 (s, 1H), 7.7 (m, 2H), 7.23 (m,1H), 6.84 (s, 1H), 6.60 (s, 1H).

The intermediate was prepared as follows

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (83mg, 0.2 mmol) in 4 ml dioxane:water (3:1) was added2-fluorophenylboronic acid (42 mg, 0.3 mmol) and potassium carbonate (66mg, 0.48 mmol). The resulting mixture was degassed for 15 minutes afterwhich Pd (PPh₃)₄ (35 mg, 0.03 mmol) was added and the mixture wasfurther degassed for 15 minutes. The reaction mixture was then heated at100° C. for 12 hours. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate and was washed with saturatedsodium bicarbonate, followed by brine. The organic phase was dried withsodium sulfate and concentrated under reduced pressure to afford crudeproduct which was purified by ISCO flash chromatography using 10%-100%EtOAc in hexane to afford 68 mg of the desired product (Yield: 81%)¹HNMR (300 MHz, CDCl₃) δ: 7.74-7.64 (m, 2H), 7.61-7.55 (m, 2H), 7.50-7.29(m, 9H), 7.28 (d, 1H), 7.15 (d, 1H), 7.09-6.99 (m, 1H), 5.67 (s, 2H),5.23 (s, 2H).

Example 8 Preparation of Compound

To a solution of 2,3-bis(benzyloxy)-6-(3-methoxyphenyl)pyridine (80 mg,0.2 mmol) in MeOH (10 ml), palladium (10 wt % on activated carbon,catalytic amount) was added. This mixture was charged with hydrogenusing balloon and the reaction was run for 16 hours. The mixture wasfiltered through Celite and was washed with MeOH (15 ml). The filtratewas evaporated under reduced pressure to afford a solid (25 mg) in 58%yield. LC/MS: Found, 217.85 (M+H).

The intermediate was prepared as follows.

a. Preparation of Compound

To a solution of intermediate 2c (6-iodo-2,3-dibenzyloxypyridine) (100mg, 0.24 mmol) in 4 ml dioxane:water (3:1) was added3-methoxyphenylboronic acid (74 mg, 0.48 mmol) and potassium carbonate(66 mg, 0.5 mmol). The resulting mixture was degassed for 15 minutesafter which Pd (PPh₃)₄ (35 mg, 0.03 mmol) was added and the mixture wasfurther degassed for 15 minutes. The reaction mixture was then heated at100° C. for 12 hours. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate and was washed with saturatedsodium bicarbonate, followed by brine. The organic phase was dried withsodium sulfate and concentrated under reduced pressure to afford crudeproduct which was purified by ISCO flash chromatography using 10-100%EtOAc in hexane to afford 90 mg of the desired product (Yield: 84%)¹HNMR (300 MHz, CDCl₃) δ: 7.57-7.53 (m, 2H), 7.51-7.3 (m, 10H), 7.26 (d,1H), 7.16 (d, 1H), 7.9-6.84 (m, 1H), 5.67 (s, 2H), 5.21 (s, 2H).

Example 9 Preparation of Compound

To a solution of 6-cyclohexenyl-2-ethoxy-3-methoxypyridine (50 mg, 0.21mmol) stirred in CH₂Cl₂ (3.0 ml) under nitrogen, was added borontribromide (1M solution in CH₂Cl₂) (1.0 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq.HCl (3N)was added. The resulting solid was filtered and then redissolved indichloromethane and washed with NaHCO₃ and brine, dried and evaporatedunder reduced pressure to afford a tan solid, yield: 34% (14 mg). ¹H NMR(300 MHz, CDCl₃) δ: 6.85 (d, J=7.8 Hz, 1H), 6.25 (s, 1H), 6.14 (d, J=7.8Hz, 1H), 2.22-2.12 (m, 4H), 1.67-1.54 (m, 4H).

The intermediates were prepared as follows:

a. Preparation of Compound

To a solution of 2-bromopyridin-3-ol (2.4 g, 13.8 mmol) in H₂O (34 ml)was added potassium carbonate (2.85 g, 20.7 mmol) followed by iodine(3.8 g, 15.2 mmol) and this mixture was stirred at room temperatureovernight. This mixture was cooled to 0° C., then slowly quenched by 2NHCl to pH=6. The resulting precipitate was collected by filtration,washed with water and dried to give 2-bromo-6-iodopyridine-3-ol (3 g,73% yield). LC/MS: 300 (M+H).

b. Preparation of Compound

To a solution of 6-iodo-2-bromopyridin 3-ol (1.7 g, 5.9 mmol) in THF (50ml), K₂CO₃ (1.22 g, 8.85 mmol) was added, and the mixture was stirredfor 10 minutes at 0° C. in an ice bath. To this mixture CH₃I (1.0 g, 7.0mmol) was then added slowly. The reaction mixture was stirred for 16hours at room temperature. The reaction mixture poured into ice water(100 ml), then extracted with EtOAc (3×), dried in Na₂SO₄ and evaporatedunder reduced pressure to afford a white solid 1.5 g (yield: 80.96%). ¹HNMR (300 MHz, CDCl₃) δ: 7.50 (d, J=8.1 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H),3.88 (s, 3H).

c. Preparation of Compound

To a solution of 6-iodo-2-bromo-3-methoxypyridine (1.5 g, 4.8 mmol) inEtOH (100 ml), NaOEt (487.6 mg) in EtOH (20 ml) was added for 30minutes. This reaction was heated to 100° C. for 2 hours. After coolingto room temperature, ethanol was removed under reduced pressure anddiluted with 50 ml water. The resulting residue was extracted withCH₂Cl₂ (3×), washed with brine, dried over Na₂SO₄ and evaporated underreduced pressure to give a crude oil, which was purified by ISCO flashchromatography using 20% EtOAc in hexanes, recovered starting material(400 mg), collected 6-iodo-2-ethoxyl-3-methoxylpyridine: 600 mg (yield:45%). ¹H NMR (300 MHz, CDCl₃) δ: 7.22 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8Hz, 1H), 4.45 (qt, J=7.5 Hz, 2H), 3.86 (s, 3H), 1.45 (t, J=4.5 Hz, 3H).

d. Preparation of Compound

A solution of 6-iodo-2-ethoxy-3-methoxy pyridine (150 mg, 0.54 mmol),cyclohexenyl pinacol ester (167 mg, 0.8 mmol), potassium carbonate (138mg, 1 mmol) in 6 mL (dioxane:water) (3:1) was degassed for 15 minutes.Pd (PPh₃)₄ (92 mg, 0.08 mmol) was then added and the resulting mixturewas heated at 100° C. overnight. The reaction mixture was cooled to roomtemperature and was diluted with ethyl acetate, washed with NaHCO₃followed by brine. The organic layer was dried over sodium sulfate,evaporated under reduced pressure to give a crude product. Purificationby ISCO flash chromatography using a gradient of 10-100% ethyl acetatein hexane afforded the pure product in 83% yield (105 mg). ¹H NMR (300MHz, CDCl₃) δ: 6.98 (d, J=6.0 Hz, 1H), 6.8 (d, J=6.0 Hz, 1H), 6.7 (m,1H), 4.5 (qt, 2H), 3.82 (s, 3H), 2.4 (m, 2H), 2.25 (m, 2H), 1.8-1.6 (m,4H), 1.43 (t, 3H).

Example 10 Preparation of Compound

To a solution of 6-(3,4-methylenedioxy)-2-ethoxy-3-methoxypyridine (50mg, 0.18 mmol) stirred in CH₂Cl₂ (3.0 ml) under nitrogen, was addedboron tribromide (1M solution in CH₂Cl₂) (0.8 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq.HCl (3N)was added. The resulting solid was filtered and then redissolved indichloromethane and washed with NaHCO₃ and brine, dried using anhydroussodium sulfate and evaporated under reduced pressure to afford a crudeproduct which was then purified in ISCO flash chromatography using 10%MeOH in CH₂Cl₂ to give the desired product, yield: 38% (15 mg). LC/MS:Found, 220 (M+H).

The intermediate was prepared as follows.

a. Preparation of Compound

A solution of 6-iodo-2-ethoxy-3-methoxy pyridine (100 mg, 0.36 mmol),3,4-methylenedioxy-phenylboronic acid (77 mg, 0.46 mmol), potassiumcarbonate (97 mg, 0.7 mmol)) in 6:2 mL (dioxane:water) was degassed for15 minutes. Pd (PPh₃)₄ (63 mg, 0.05 mmol) was then added and theresulting mixture was heated at 100° C. overnight. The reaction mixturewas cooled to room temperature and was diluted with ethyl acetate,washed with NaHCO₃ followed by brine. The organic layer was dried oversodium sulfate, evaporated under reduced pressure to give a crudeproduct. Purification in ISCO using 10-100% ethyl acetate in hexaneafforded the pure product in 100% yield (100 mg). ¹H NMR (300 MHz,CDCl₃) δ: 7.45 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H),6.84 (d, J=9.0 Hz, 1H), 5.97 (s, 2H), 4.55 (qt, J=9.0 Hz, 2H), 3.87 (s,3H), 1.47 (t, J=7.2 Hz, 3H).

Example 11 Preparation of Compound

To a solution of 6-cyclohexyl-2-ethoxy-3-methoxypyridine (25 mg, 0.11mmol) stirred in CH₂Cl₂ (3.0 ml) under nitrogen, was added borontribromide (1M solution in CH₂Cl₂) (0.8 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq.HCl (3N)was added. The resulting solid was filtered and then redissolved inCH₂Cl₂ and washed with NaHCO₃ and brine, dried using anhydrous sodiumsulfate and evaporated under reduced pressure to afford a crude productwhich was then purified by ISCO flash chromatography using 10% MeOH inCH₂Cl₂ to give the desired product, yield: 49% (10 mg). ¹H NMR (300 MHz,CDCl₃) δ: 6.83 (d, J=6.0 Hz, 1H), 5.98 (d, J=6.0 Hz, 1H), 2.5-1.3 (m,11H).

The intermediate was prepared as follows.

a. Preparation of Compound

To a solution of 6-(cyclohexen-1-yl)-2-ethoxy-3-methoxypyridine (seeExample 9 part d) (50 mg, 0.214 mmol) in MeOH (10.0 ml), palladium 10 wt% on activated carbon (catalytic amount) was added. This mixture wascharged with hydrogen using balloon and the reaction was run for 16hours. The mixture was filtered on Celite and was washed with MeOH (15ml). The filtrate was evaporated under reduced pressure to afford asolid (30 mg) in 60% yield. ¹H NMR (300 MHz, CDCl₃) δ: 6.92 (d, J=6.0Hz, 1H), 6.6 (d, J=6.0 Hz, 1H), 4.46 (qt, J=6.3 Hz, 2H), 3.81 (s, 3H),2.5 (m, 1H), 1.9-1.3 (m, 13H).

Example 12 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-bis(4-fluorophenyl)pyridine (100 mg,0.3 mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide(1.0 M solution in CH₂Cl₂) (1.5 ml). After addition was completed, thereaction mixture was stirred for 16 hours at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered, which wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine, dried usinganhydrous sodium sulfate and evaporated under reduced pressure to afforda solid (80 mg), yield: 87%. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.66 (m, 2H),7.6 (m, 2H), 7.46 (m, 2H), 7.20 (d, J=6.0 Hz, 2H), 7.08 (m, 1H), 6.7 (d,1H), 6.28 (d, 1H). LC/MS: 300.20 (M+H).

The intermediates were prepared as follows:

a. Preparation of Compound

To a solution of commercially available 2,3-dimethoxypyridine (2.0 g,14.7 mmol) and NaOAc (5.4 g, 44 mmol) in AcOH (25 ml) at 0° C. was addeda solution of bromine (2.0 ml, 36.6 mmol) in AcOH (0.5 ml). The coolingbath was removed and the reaction was then stirred at room temperaturefor 16 hours. The mixture was poured into crushed ice followed byneutralization with 25% aqueous NaOH solution, the aqueous phase wasextracted with CH₂Cl₂ (3×). The combined organic phases were dried overNa₂SO₄ and concentrated. Purification by ISCO flash chromatography usinga gradient of 10-15% EtOAc in hexanes provided the desired product 3.86g, tan solid (89%): ¹H NMR (300 MHz, CDCl₃) δ: 7.18 (s, 1H), 3.98 (s,3H), 3.84 (s, 3H).

b. Preparation of Compound

The mixture of 5,6-dibromo-2,3-dimethoxypyridine (260 mg, 0.87 mmol),4-fluorophenylboronic acid (367 mg, 3.0 mmol), Pd(PPh₃)₄ (303 mg, 0.26mmol) and K₂CO₃ (414 mg, 3.0 mmol) in 1,4-dioxane (4.0 mL) and H₂O (1.0ml) was degassed for 30 minutes. This mixture was heated to 100° C. andstirred for 16 hours. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 210 mg of thedesired product, yield: 73%. ¹H NMR (300 MHz, CDCl₃) δ: 7.35 (m, 2H),7.20 (m, 2H), 7.20 (m, 2H), 7.17 (m, 2H), 7.04-6.98 (m, 4H), 4.18 (s,3H), 3.01 (s, 3H). LC/MS: 328.205 (M+H).

Example 13 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-(3-fluorophenyl) pyridine (200 mg,0.61 mmol) in CH₂Cl₂ (6.0 ml) under nitrogen, was added boron tribromide(1.0 M solution in CH₂Cl₂) (2.0 ml). After addition was completed, thereaction mixture was stirred for 16 hours at room temperature. CH₂Cl₂was removed from the reaction mixture followed by addition of HCl (3N).The resulting solid was filtered which was redissolved in CH₂Cl₂ andwashed with NaHCO₃ and brine, dried and evaporated under reducedpressure to afford a solid (160 mg), yield: 87%. ¹H NMR (300 MHz,DMSO-d₆) δ: 7.2-7.10 (m, 4H), 7.06-7.03 (m, 4H), 6.80 (s, 1H). LC/MS:300.202 (M+H).

The intermediate was prepared as follows.

a. Preparation of Compound

The mixture of 5,6-dibromo-2,3-dimethoxypyridine (260 mg, 0.87 mmol),3-fluorophenylboronic acid (367 mg, 3.6 mmol), Pd(PPh₃)₄ (300 mg, 0.26mmol) and K₂CO₃ (731 mg, 5.3 mmol) in 1,4-dioxane (5.0 mL) and H₂O (1.5ml) was degassed for 30 minutes. This mixture was heated to 100° C. andstirred for 16 hours. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 190 mg of thedesired product, yield: 66%. ¹H NMR (300 MHz, CDCl₃) δ: 7.25 (m, 2H),7.05 (m, 2H), 7.0-6.8 (m, 5H), 4.04 (s, 3H), 3.87 (s, 3H).

Example 14 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-(diphenyl)pyridine (130 mg, 0.45mmol) in CH₂Cl₂ (6.0 ml) under nitrogen, was added boron tribromide (2.0ml of a 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 16 hours at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford asolid (60 mg), yield: 55%. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.58 (m, 6H),7.23 (t, 1H), 7.15 (m, 1H), 7.07 (t, 1H), 6.7 (d, J=7.2 Hz, 1H).

The intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (150 mg, 0.5 mmol,phenylboronic acid (242 mg, 2.0 mmol), Pd(PPh₃)₄ (231 mg, 0.2 mmol) andK₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (5.0 mL) and H₂O (1.5 ml) wasdegassed for 30 minutes. This mixture was heated to 100° C. and stirredfor 16 hours. The reaction mixture was cooled to room temperature andpartitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl (1×).The organic phase was dried over Na₂SO₄ and was concentrated undervacuum. The resulting residue was purified by ISCO flash chromatographyusing 10% EtOAc in hexane to give 130 mg of the desired product, yield:89%. ¹H NMR (300 MHz, CDCl₃) δ: 7.35 (m, 2H), 7.20 (m, 2H), 7.20 (m,2H), 7.17 (m, 2H), 7.04-6.98 (m, 4H), 4.18 (s, 3H), 3.01 (s, 3H). LC/MS:328.205 (M+H). ¹H NMR (300 MHz, CDCl₃) δ: 7.4 (m, 2H), 7.29 (m, 3H),7.24-7.21 (m, 5H), 7.12 (s, 1H), 4.15 (s, 3H), 3.96 (s, 3H). LC/MS:292.23 (M+H).

Example 15 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-(4-nitrophenyl)pyridine (50 mg, 0.13mmol) in CH₂Cl₂ (4.0 ml) under nitrogen, was added boron tribromide (1.0M solution in CH₂Cl₂) (1.0 ml). After addition was completed, thereaction mixture was stirred for 16 hours at room temperature. CH₂Cl₂was removed from the reaction mixture followed by addition of HCl (3N).The resulting solid was filtered which was redissolved in CH₂Cl₂ andwashed with NaHCO₃ and brine, dried and evaporated under reducedpressure to afford a solid (35 mg), yield: 76%. ¹H NMR (300 MHz,DMSO-d₆) δ: 8.14-8.06 (m, 4H), 7.45 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 6.93 (s, 1H). LC/MS: 354.07 (M+H).

The intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (296 mg, 1.0 mmol,4-nitrophenyl pinacol boronate ester 996 mg, 4.0 mmol), Pd(PPh₃)₄ (462mg, 0.4 mmol) and K₂CO₃ (552 mg, 4.0 mmol) in 1,4-dioxane (5.0 mL) andH₂O (1.5 ml) was degassed for 30 minutes. This mixture was heated to100° C. and stirred for 16 hours. The reaction mixture was cooled toroom temperature and partitioned between NaHCO₃ and EtOAc (3×), andwashed with NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 150 mg of thedesired product, yield: 39%. ¹H NMR (300 MHz, CDCl₃) δ: 8.15 (d, J=9.0Hz, 2H), 8.06 (d, J=9.0 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7Hz, 2H), 7.05 (s, 1H), 4.10 (s, 3H), 3.96 (s, 3H).

Example 16 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-bis(4-carboxyamidophenyl)pyridine (50mg, 0.123 mmol) in CH₂Cl₂ (4.0 ml) under nitrogen, was added borontribromide (1.5 ml, 1.0 M solution in CH₂Cl₂). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed from the reaction mixturefollowed by addition of HCl (3N). The resulting solid was filtered. Thesolid was then redissolved in CH₂Cl₂ and washed with NaHCO₃ and brine,dried using anhydrous sodium sulfate and evaporated under reducedpressure to afford a solid (25 mg), yield: 54%. ¹H NMR (300 MHz, DMSOd₃) δ: 8.0 (s, 1H), 7.93 (s, 1H), 7.76 (m, 4H), 7.42 (s, 1H), 7.34 (s,1H), 7.22 (d, J=9.0 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 6.85 (s, 1H).

The intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (296 mg, 1.0 mmol),4-carboxamidophenyl boronic acid (659 mg, 4.0 mmol-4 equiv), Pd(PPh₃)₄(462 mg, 0.4 mmol) and K₂CO₃ (552 mg, 4.0 mmol) in 1,4-dioxane (5.0 mL)and H₂O (1.5 ml) was degassed for 30 minutes. This mixture was heated to100° C. and stirred for 16 hours. The reaction mixture was cooled toroom temperature and partitioned between NaHCO₃ and EtOAc (3×), andwashed with NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 250 mg of thedesired product, yield: 66%; ¹H NMR (300 MHz, MeOD-d₄) δ: 7.70 (d, J=8.1Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.19 (m, 3H),3.95 (s, 3H), 3.83 (s, 3H).

Example 17 Preparation of Compound

To a solution of 2,3-dimethoxy-5,6-bis(3-carboxyamidophenyl)pyridine (50mg, 0.123 mmol) in CH₂Cl₂ (4.0 ml) under nitrogen, was added borontribromide (1.5 ml, 1.0 M solution in CH₂Cl₂). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. The dichloromethane was removed from the reaction mixturefollowed by addition of HCl (3N). The resulting solid was filtered whichwas redissolved in CH₂Cl₂ and washed with NaHCO₃ and brine, dried andevaporated under reduced pressure to afford a solid (19 mg), yield: 41%.¹H NMR (300 MHz, DMSO d₃) δ:7.89 (d, J=6.0 Hz, 1H), 7.8-7.63 (m, 3H),7.37-7.10 (m, 4H), 7.0 (d, J=6.0 Hz, 1H), 6.89 (s, 1H).

The intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (200 mg, 0.67 mmol),3-carboxamidophenyl boronic acid (442 mg, 2.68 mmol-4 equiv.), Pd(PPh₃)₄(346 mg, 0.3 mmol) and K₂CO₃ (250 mg, 1.8 mmol) in 1,4-dioxane (4.0 mL)and H₂O (1.0 ml) was degassed for 30 minutes. This mixture was heated to100° C. and stirred for 16 hours. The reaction mixture was cooled toroom temperature and partitioned between NaHCO₃ and EtOAc (3×), andwashed with NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 160 mg of thedesired product, yield: 63%; ¹H NMR (300 MHz, MeODd₄) δ: 7.86 (s, 1H),7.74 (s, 1H), 7.68-7.59 (m, 2H), 7.29-7.14 (m, 5H), 3.96 (s, 3H), 3.83(s, 3H).

Example 18 Preparation of Compound

To a solution of 5,6-dibromo-2,3-dimethoxypyridine (120 mg, 0.4 mmol) inCH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide (1.2 ml, 1.0M solution in CH₂Cl₂). After addition was completed, the reactionmixture was stirred for 16 hours at room temperature. Methylenechloridewas removed from the reaction mixture followed by addition of HCl (3N).The resulting solid was filtered. The solid was then redissolved inCH₂Cl₂ and washed with NaHCO₃ and brine, dried using anhydrous sodiumsulfate and the organic phase evaporated under reduced pressure toafford a solid (80 mg), yield: 74%. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.3 (s,1H).

Example 19 Preparation of Compounds

To a mixture of substituted 2,3-dimethoxy-5-bromo-6-phenylpyridine and2,3-dimethoxy-5-phenyl-6-bromopyridine (85 mg, 0.27 mmol) in CH₂Cl₂ (3.0ml) under nitrogen, was added boron tribromide (1.0 ml. 1.0 M solutionin CH₂Cl₂). After addition was completed, the reaction mixture wasstirred for 16 hours at room temperature. The dichloromethane wasremoved from the reaction mixture followed by addition of HCl (3N) tothe residue. The resulting solid was filtered. The solid was redissolvedin CH₂Cl₂ and washed with NaHCO₃ and brine, dried using anhydrous sodiumsulfate and evaporated under reduced pressure to afford a solid (70 mg),yield: 90%. LC/MS: Calculated 284. found: 284.29, 286.23. Rt=2.47 (39%),2.97 (61%).

The intermediate was prepared as follows.

a. Preparation of Compounds

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (296 mg, 1.0 mmol),4-fluorophenylboronic acid (167 mg, 1.2 mmol-1.2 equiv), Pd(PPh₃)₄ (138mg, 0.12 mmol) and K₂CO₃ (272 mg, 2.0 mmol) in 1,4-dioxane (3.0 mL) andH₂O (1.0 ml) was degassed for 30 minutes. This mixture was heated to100° C. and stirred for 16 hours. The reaction mixture was cooled toroom temperature and partitioned between NaHCO₃ and EtOAc (3×), andwashed with NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 85 mg of thedesired (1:1) mixture of products, yield: 27%; ¹H NMR (300 MHz, CDCl₃)δ: 7.29-7.25 (m, 2H), 7.11 (m, 2H), 6.98-6.87 (m, 4H), 4.07 (s, 3H),3.91 (s, 3H).

Example 20 Preparation of Compounds

To a mixture of the disubstituted dimethoxypyridine (120 mg, 0.38 mmol)in CH₂Cl₂ (4.0 ml) under nitrogen, was added boron tribromide (1.2 ml,1.0 M solution in CH₂Cl₂). After addition was completed, the reactionmixture was stirred for 16 hours at room temperature. The dichoromethanewas removed from the reaction mixture followed by addition of HCl (3N)to the residue. The resulting solid was filtered. The solid was thenredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine, dried usinganhydrous sodium sulfate and evaporated under reduced pressure to afforda solid (85 mg), yield: 78%. LC/MS: Calculated, 284. found: 284.25,286.20, Rt=2.20 (36%), 2.48 (64%).

The intermediate was prepared as follows.

a. Preparation of Compounds

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (296 mg, 1.0 mmol),3-fluorophenylboronic acid (168 mg, 1.2 mmol-1.2 equiv-), Pd(PPh₃)₄ (138mg, 0.12 mmol) and K₂CO₃ (272 mg, 2.0 mmol) in 1,4-dioxane (3.0 mL) andH₂O (1.0 ml) was degassed for 30 minutes. This mixture was heated to100° C. and stirred for 16 hours. The reaction mixture was cooled toroom temperature and partitioned between NaHCO₃ and EtOAc (3×), andwashed with NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated under vacuum. The resulting residue was purified by ISCOflash chromatography using 10% EtOAc in hexane to give 120 mg of thedesired mixture (1:1) of products, yield: 38%; ¹H NMR (300 MHz, CDCl₃)δ: 7.5 (m, 1H), 7.43-7.31 (m, 2H), 7.23 (s, 1H), 7.10-7.01 (m, 1H), 3.99(s, 3H), 3.87 (s, 3H).

Example 21 Preparation of Compound

To a solution of 2-ethoxy-3-methoxy-5-(4-fluorophenyl)pyridine (30 mg,0.12 mmol) stirred in CH₂Cl₂ (1.0 ml) under nitrogen, was added borontribromide (1M solution in CH₂Cl₂) (0.5 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq.HCl (3N)was added. The resulting solid was filtered and then redissolved inCH₂Cl₂ and washed with NaHCO₃ and brine, dried and evaporated underreduced pressure to afford a tan solid 19 mg (77% yield). ¹H NMR (300MHz, DMSO-d₆) δ: 9.19 (s, 1H), 7.51 (m, 2H), 7.14 (m, 3H).

The intermediates were prepared as follows.

a. Preparation of Compound

To a solution of intermediate 2c (2-ethoxy-3-methoxy-5-bromopyridine)(140 mg, 0.5 mmol) in 4 ml dioxane:water (3:1) was added4-(fluoromethyl)phenylboronic acid (104 mg, 0.75 mmol) and potassiumcarbonate (138 mg, 1.0 mmol). The resulting mixture was degassed for 15minutes after which Pd (PPh₃)₄ (60 mg, 0.06 mmol) was added and themixture was further degassed for 15 minutes. The reaction mixture wasthen heated at 100° C. for 12 hours. After cooling to room temperature,the reaction mixture was diluted with ethyl acetate and was washed withsaturated sodium bicarbonate, followed by brine. The organic phase wasdried with sodium sulfate and concentrated under reduced pressure toafford crude product which was purified by ISCO flash chromatographyusing 10%-100% EtOAC in hexane to afford 119 mg product pure product(yield: 96%); ¹H NMR (300 MHz, CDCl₃) δ: 7.84 (s, 1H), 7.44 (m, 2H),7.14-7.08 (m, 3H), 4.46 (qt, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.44 (qt,J=7.2 Hz, 3H).

Example 22 Preparation of Compound

To a solution of 2-ethoxy-3-methoxy-6-bromo-5-(4-fluorophenyl)pyridine(30 mg, 0.08 mmol) stirred in CH₂Cl₂ (4.0 ml) under nitrogen, was addedboron tribromide (1M solution in CH₂Cl₂) (0.5 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq. HCl (3N)was added. The resulting solid was filtered and then redissolved inCH₂Cl₂ and washed with NaHCO₃ and brine, dried and evaporated underreduced pressure to afford a solid (15 mg (60% yield). ¹H NMR (300 MHz,DMSO-d₆) δ: 7.39 (m, 2H), 7.23 (m, 2H), 6.95 (s, 1H).

The intermediates were prepared as follows.

a. Preparation of Compound

To a mixture of 21a (2-ethoxy-3-methoxy-5-(4-fluorophenyl)pyridine) (85mg, 0.34 mmol) in acetic acid (1.0 mL) was added sodium acetate (187 mg,1.4 mmol). The reaction mixture was cooled to −32° C. and Br₂ (0.008 mL)in acetic acid (0.3 mL) was added dropwise. The reaction mixture wasstirred at this temperature for 2 h. The temperature of the cooling bathwas raised to 0° C. and the stirring was continued for 1 h. To thismixture 25% NaOH was added at 0° C. until pH 6 and then extracted withdichloromethane three times. The organic layer wad dried, concentratedand purified by ISCO using 5% EtOAC in hexane to afford a white solid aspure product 65 mg (58% yield). ¹H NMR (300 MHz, CDCl₃) δ: 7.38-7.34 (m,2H), 7.13-7.07 (m, 2H), 6.96 (s, 1H), 4.47 (qt, J=7.2 Hz, 2H), 3.85 (s,3H), 1.45 (qt, J=7.2 Hz, 3H). LC/MS: 332 (M+H).

Example 23 Preparation of Compound

To a solution of 2-ethoxy-3-methoxy-5-bromo-6-(4-fluorophenyl)pyridine(30 mg, 0.9 mmol) stirred in CH₂Cl₂ (1.0 ml) under nitrogen, was addedboron tribromide (1M solution in CH₂Cl₂) (0.5 ml). After addition wascompleted, the reaction mixture was stirred for 16 hours at roomtemperature. Dichloromethane was removed under vacuum and aq.HCl (3N)was added. The resulting solid was filtered and then redissolved inCH₂Cl₂ and washed with NaHCO₃ and brine, dried and evaporated underreduced pressure to afford a tan solid. ¹H NMR (300 MHz) (DMSO-d₆) δ9.75 (bs, 1H), 8.46 (bs, 1H), 7.49-7.26 (m, 4H), 6.96 (s, 1H).

The intermediates were prepared as follows.

a. Preparation of Compound

To a solution of intermediate 9c (2-ethoxy-3-methoxy-6-iodopyridine)(140 mg, 0.5 mmol) in 4 ml dioxane:water (3:1) was added4-(fluoro)phenylboronic acid (104 mg, 0.75 mmol) and potassium carbonate(138 mg, 1.0 mmol). The resulting mixture was degassed for 15 minutesafter which Pd (PPh₃)₄ (60 mg, 0.06 mmol) was added and the mixture wasfurther degassed for 15 minutes. The reaction mixture was then heated at100° C. for 12 hours. After cooling to room temperature, the reactionmixture was diluted with ethyl acetate and was washed with saturatedsodium bicarbonate, followed by brine. The organic phase was dried withsodium sulfate and concentrated under reduced pressure to afford crudeproduct which was purified by ISCO flash chromatography using 10%-100%EtOAC in hexane to afford 120 mg product pure product (yield: 97%); ¹HNMR (300 MHz, CDCl₃) δ: 7.97-7.92 (m, 2H), 7.26-7.05 (m, 4H), 4.59 (qt,J=6.9 Hz, 2H), 3.92 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).

b. Preparation of Compound

To a mixture of 23a (2-ethoxy-3-methoxy-6-(4-fluorophenyl)pyridine) (120mg, 0.48 mmol) in acetic acid (2.0 mL) was added sodium acetate (264 mg,1.9 mmol). The reaction mixture was cooled to −32° C. and Br₂ (0.013 mL)in acetic acid (1.0 mL) was added dropwise. The reaction mixture wasstirred at this temperature for 2 hours. The temperature of the coolingbath was raised to 0° C. and the stirring was continued for 1 hour. Tothis mixture 25% NaOH was added at 0° C. until pH 6 and then extractedwith dichloromethane three times. Organic layer wad dried, concentratedand purified by ISCO using 10% EtOAC in hexane to afford a white solidas pure product 86 mg (55% yield). ¹H NMR (300 MHz, MeOD-d₄) δ:7.73-7.68 (m, 2H), 7.48 (s, 1H), 7.18-7.13 (m, 2H), 4.43 (qt, J=7.2 Hz,2H), 3.90 (s, 3H), 1.40 (t, J=7.2 Hz, 3H). LC/MS: 326 (M+H).

Example 24 Preparation of Compound

6-(4-Fluorophenyl)-5-hydroxypyrimidin-4(3H)-one

6-(4-Fluorophenyl)-5-methoxypyrimidin-4(3H)-one (107 mg, 0.49 mmol) wasdissolved in anhydrous DCM (5 mL). The reaction mixture was cooled to 0°C. and the 1M in DCM BBr₃ (5 mL, 5 mmol) was added. It was then allowedto warm to room temperature and stirred for 24 hours. Then, the solventwas removed under reduced pressure. The resulting residue was dilutedwith EtOAc, which was washed with sat. NaHCO₃ followed by brine. Theorganic layer was dried over Na₂SO₄ followed by concentration under thevacuum. The residue was then flash chromatographed on silica gel elutingwith 0-10% MeOH/DCM to provide6-(4-fluorophenyl)-5-hydroxypyrimidin-4(3H)-one as a white solid (50 mg,50%); m.p. 285-287° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.67 (bs, 1H), 9.83(bs, 1H), 8.20 (dd, J=9 Hz, J=6 Hz, 2H), 7.87 (s, 1H), 7.29-7.25 (m,2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 161.9 (J_(C,F)=245 Hz), 158.7, 141.1,138.5, 136.0, 132.3, 130.7 (J_(C,F)=8 Hz), 114.8 (J_(C,F)=21 Hz); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −113.0;

a. Preparation of Compound

4-Chloro-5,6-dimethoxypyrimidine

4,6-Dichloro-5-methoxypyrimidine (300 mg, 1.68 mmol) was added to MeOH(10 mL). Then the reaction mixture was cooled to 0° C. It was treatedwith NaOMe (99 mg, 1.85 mmol) and allowed to warm to room temperature.The reaction mixture was then stirred for 19 hours at room temperature.After the reaction was completed, it was put under the vacuum to removeMeOH. The resulting residue was diluted with EtOAc, which was thenwashed with sat. NH₄Cl followed by brine. The organic layer was driedover Na₂SO₄ and then concentrated. The residue was flash chromatographedon silica gel eluting with 0 to 10% EtOAc/Hexane to provide4-chloro-5,6-dimethoxypyrimidine as a white solid (168 mg, 57%); m.p.53-55° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 4.03 (s, 3H), 3.88(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.6, 151.6, 151.3, 138.2, 60.7,54.8.

b. Preparation of Compound

4-(4-Fluorophenyl)-5,6-dimethoxypyrimidine

4-Chloro-4,5-dimethoxypyrimidine (165 mg, 0.95 mmol),(4-fluorophenyl)boronic acid (99 mg, 1.42 mmol), Pd(PPh₃)₄ (110 mg,0.095 mmol) and Na₂CO₃ (300 mg, 2.84 mmol) were dissolved in a mixtureof dioxane (9 mL) and water (3 mL). The air was evacuated and replacedwith N₂. Then, the reaction mixture was refluxed for 19 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure and the resulting residue was flash chromatographed on silicagel eluting with 0 to 10% EtOAc/Hexane. This afforded4-(4-fluorophenyl)-5,6-dimethoxypyrimidine as a white solid (181 mg,82%); m.p.62-64° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.07 (dd,J=9 Hz, J=6 Hz, 2H), 7.15-7.11 (m, 2H), 4.07 (s, 3H), 3.73 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 163.7 (J_(C,F)=249 Hz), 164.0, 154.3, 152.0,139.4, 131.4 (J_(C,F)=8 Hz), 131.3, 115.3 (J_(C,F)=21 Hz), 60.2, 54.2;¹⁹F NMR (376 MHz, CDCl₃) δ −111.0;

-   -   c. Preparation of Compound

6-(4-Fluorophenyl)-5-methoxypyrimidin-4(3H)-one

4-(4-Fluorophenyl)-5,6-dimethoxypyrimidine (134 mg 0.57 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 12 hours. It was then cooled to roomtemperature. The reaction mixture was put under the vacuum to remove thesolvent, which gave white residue. This residue was diluted with waterand filtered. The solid was collected and gave6-(4-fluorophenyl)-5-methoxypyrimidin-4(3H)-one as a white solid (109mg, 87%); m.p.204-206° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H),8.07 (s, 1H), 8.04 (dd, J=9 Hz, J=6 Hz, 2H), 7.33-7.28 (m, 2H), 3.34 (s,3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.5 (J_(C,F)=246 Hz), 158.8, 147.4,143.7, 142.9, 131.7, 131.2 (J_(C,F)=8 Hz), 115.0 (J_(C,F)=21 Hz), 58.8;¹⁹F NMR (376 MHz, DMSO-d₆) δ −111.8

Example 25 Preparation of Compound

2-(4-Fluorophenyl)-5-hydroxypyrimidin-4(3H)-one

2-(4-Fluorophenyl)-5-methoxypyrimidin-4(3H)-one (58 mg, 0.26 mmol) wasdissolved in anhydrous DCM (5 mL). The reaction mixture was cooled to 0°C. and the 1M in DCM BBr₃ (3 mL, 3 mmol) was added. It was then allowedto warm to room temperature and stirred for 24 hours. Then, the solventwas removed under reduced pressure. The resulting residue was suspendedin water. It was filtered and the solid was collected and dried undervacuum to provide 2-(4-fluorophenyl)-5-hydroxypyrimidin-4(3H)-one as awhite solid (23 mg, 42%); m.p.252-254° C.; ¹H NMR (400 MHz, DMSO-d₆) δ12.88 (bs, 1H), 9.64 (bs, 1H), 8.05 (dd, J=9 Hz, J=5 Hz, 2H), 7.54 (s,1H), 7.33-7.29 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.4 (J_(C,F)=246Hz), 159.0, 146.9, 143.4, 131.7, 129.4 (J_(C,F)=9 Hz), 129.1, 115.5(J_(C,F)=22 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.5;

a. Preparation of Compound

2-Chloro-4,5-dimethoxypyrimidine

2,4-Dichloro-5-methoxypyrimidine (2.37 g, 13.2 mmol) and K₂CO₃ (1.8 g,13.2 mmol) were dissolved in MeOH (50 mL) and stirred for 19 hours atroom temperature. The solvent was removed under reduced pressure. Theresulting residue was dissolved in EtOAc and washed with distilled waterfollowed by brine. The organic layer was dried over Na₂SO₄ andconcentrated. It was then flash chromatographed on silica gel elutingwith 0 to 20% EtOAc/Hexane to give 2-chloro-4,5-dimethoxypyrimidine as awhite solid (1.70 g, 73%); m.p.65-67° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.84(s, 1H), 4.03 (s, 3H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.2,150.0, 141.7, 138.2, 56.6, 55.0.

b. Preparation of Compound

2-(4-Fluorophenyl)-4,5-dimethoxypyrimidine

2-Chloro-4,5-dimethoxypyrimidine (500 mg, 2.86 mmol),(4-fluorophenyl)boronic acid (601 mg, 4.30 mmol), Pd(PPh₃)₄ (330 mg,0.29 mmol) and Na₂CO₃ (910 mg, 8.59 mmol) were dissolved in a mixture ofdioxane (12 mL) and water (4 mL). The air was evacuated and replacedwith N₂. Then, the reaction mixture was refluxed for 5 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure and the resulting residue was flash chromatographed on silicagel eluting with 0 to 10% EtOAc/Hexane. This afforded2-(4-fluorophenyl)-4,5-dimethoxypyrimidine as a white solid (123 mg,77%); m.p.114-116° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.37 (dd, J=9 Hz, J=6Hz, 2H), 8.12 (s, 1H), 7.16-7.12 (m, 2H), 4.17 (s, 3H), 3.98 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 163.1 (J_(C,F)=248 Hz), 159.7, 155.3, 141.0,137.2, 133.6 (J_(C,F)=3 Hz), 129.6 (J_(C,F)=8 Hz), 115.3 (J_(C,F)=22Hz), 56.4, 54.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −111.9.

c. Preparation of Compound

2-(4-Fluorophenyl)-5-methoxypyrimidin-4(3H)-one

2-(4-Fluorophenyl)-4,5-dimethoxypyrimidine (187 mg, 0.799 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 12 hours. It was then cooled to roomtemperature. The reaction mixture was diluted with EtOAc and washed withsat. NaHCO₃ followed by brine. The organic layer was dried over Na₂SO₄and concentrated. The resulting residue was flash chromatographed onsilica gel eluting with 50% to 100% EtOAc/Hexane to give2-(4-fluorophenyl)-5-methoxypyrimidin-4(3H)-one as white solid (41 mg,23%); m.p.229-231° C.; ¹H NMR (400 MHz, DMSO-d₆) δ12.79 (s, 1H), 7.68(s, 1H), 8.08 (dd, J=9 Hz, J=5 Hz, 2H), 7.35-7.30 (m, 2H), 3.79 (s, 3H);¹³C NMR (100 MHz, DMSO-d₆) δ 163.6 (J_(C,F)=247 Hz), 158.1, 148.4,145.4, 130.4, 129.6 (J_(C,F)=9 Hz), 129.1, 115.5 (J_(C,F)=22 Hz), 56.0;¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.2.

Example 26 Preparation of Compound

4-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile

4-(5-Methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile (50 mg, 0.22mmol) was dissolved in anhydrous DCM (5 mL). The reaction mixture wascooled to 0° C. and the 1M in DCM BBr₃ (2.2 mL, 2.2 mmol) was added. Itwas then allowed to warm to room temperature and stirred for 18 hours.Then, the solvent was removed under reduced pressure. The resultingresidue was suspended in water. It was filtered and the solid wascollected and dried under vacuum to provide4-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile as a whitesolid (15 mg, 32%); m.p.324-326° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.05(bs, 1H), 9.91 (bs, 1H), 8.18 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H),7.64 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 158.8, 132.5, 129.4, 127.6,127.2, 127.1, 126.7, 118.4, 112.5.

a. Preparation of Compound

4-(4,5-dimethoxypyridin-2-yl)benzonitrile

2-Chloro-4,5-dimethoxypyrimidine (100 mg, 0.57 mmol),(4-cyanophenyl)boronic acid (126 mg, 0.86 mmol), Pd(PPh₃)₄ (66 mg, 0.06mmol) and Na₂CO₃ (182 mg, 1.72 mmol) were dissolved in a mixture ofdioxane (9 mL) and water (3 mL). The air was evacuated and replaced withN₂. Then, the reaction mixture was refluxed for 4 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo and theresulting residue was flash chromatographed on silica gel eluting with 0to 20% EtOAc/hexane. This afforded4-(4,5-dimethoxypyrimidin-2-yl)benzonitrile as a white solid (69 mg,74%); m.p.170-172° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=9 Hz, 2H),8.18 (s, 1H), 7.76 (d, J=9 Hz, 2H), 4.20 (s, 3H), 4.02 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 159.8, 154.0, 141.8, 141.5, 137.0, 132.3, 128.0,119.0, 113.0, 56.4, 54.2.

b. Preparation of Compound

4-(5-Methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile

4-(4,5-Dimethoxypyrimidin-2-yl)benzonitrile (53 mg, 0.22 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 5 hours. It was then cooled to roomtemperature. The reaction mixture was diluted with EtOAc and washed withsat. NaHCO₃ followed by brine. The organic layer was dried over Na₂SO₄and concentrated. The resulting residue was flash chromatographed onsilica gel eluting with 0 to 5% MeOH/DCM to give4-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile as a whitesolid (50 mg, 100%); m.p.297-299° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.99(bs, 1H), 8.19 (d, J=8 Hz, 2H), 7.96 (d, J=8 Hz, 2H), 7.75 (s, 1H), 3.81(s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) 157.8, 147.4, 146.2, 136.5, 132.5,130.0, 127.8, 118.4, 112.8, 56.1.

Example 27 Preparation of Compound

2-(4-(1H-Tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3H)-one

4-(5-Hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile (68 mg, 0.32mmol) and NaN₃ (79 mg, 1.21 mmol) were dissolved in anhydrous DMF (1mL). The reaction mixture was treated with 2 drops of acetic acid. Itwas sealed and then it was heated at 130° C. for 17 hours. The reactionwas cooled to room temperature and gave brownish suspension. DMF wasremoved by Kugelrohr distillation. The resulting residue was suspendedin water and filtered to give2-(4-(1H-tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3H)-one as a darkbrown solid (42 mg, 51%); ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=9 Hz,2H), 8.03 (d, J=8 Hz, 2H), 7.55 (s, 1H).

Example 28 Preparation of Compound

3-(5-Hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile

3-(5-Methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile (50 mg, 0.219mmol) was dissolved in anhydrous DCM (5 mL). The reaction mixture wascooled to 0° C. and the 1M in DCM BBr₃ (2.2 mL, 2.2 mmol) was added. Itwas then allowed to warm to room temperature and stirred for 18 hours.Then, the solvent was removed under reduced pressure. The resultingresidue was suspended in water. It was filtered and the solid wascollected and dried under vacuum to provide3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile as a whitesolid (27 mg, 58%); m.p.294-296° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.44(s, 1H), 8.35 (d, J=8 Hz, 1H), 7.93 (d, J=8 Hz, 1H), 7.68 (t, J=8 Hz,1H), 7.61 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.3, 146.4, 143.9,134.3, 133.4, 131.9, 131.5, 130.4, 129.8, 118.4, 111.7.

a. Preparation of Compound

3-(4,5-Dimethoxypyrimidin-2-yl)benzonitrile

2-Chloro-4,5-dimethoxypyrimidine (100 mg, 0.57 mmol),(3-cyanophenyl)boronic acid (126 mg, 0.86 mmol), Pd(PPh₃)₄ (66 mg, 0.06mmol) and Na₂CO₃ (182 mg, 1.72 mmol) were dissolved in a mixture ofdioxane (9 mL) and water (3 mL). The air was evacuated and replaced withN₂. Then, the reaction mixture was refluxed for 5 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo and theresulting residue was flash chromatographed on silica gel eluting with 0to 20% EtOAc/Hexane. This afforded3-(4,5-dimethoxypyrimidin-2-yl)benzonitrile as a white solid (138 mg,100%); m.p.134-136° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H), 8.54 (d,J=8 Hz, 1H), 8.09 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H),4.13 (s, 3H), 3.95 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 159.8, 153.6,141.7, 138.5, 137.0, 132.8, 131.6, 131.3, 129.2, 118.9, 112.6, 56.4,54.2.

b. Preparation of Compound

3-(5-Methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile

3-(4,5-Dimethoxypyrimidin-2-yl)benzonitrile (138 mg, 0.57 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 6 hours. It was then cooled to roomtemperature. The reaction mixture was diluted with EtOAc and washed withsat. NaHCO₃ followed by brine. The organic layer was dried over Na₂SO₄and concentrated. The resulting residue was flash chromatographed onsilica gel eluting with 0 to 10% MeOH/DCM to give3-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile as a whitesolid (56 mg, 43%); m.p.255-257° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.93(bs, 1H), 8.44 (s, 1H), 8.34 (d, J=8 Hz, 1H), 7.99 (d, J=8 Hz, 1H),7.74-7.70 (m, 2H), 3.82 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.9,147.5, 145.9, 133.9, 133.7, 131.7, 130.7, 130.4, 129.9, 118.3, 111.7,56.1.

Example 29 Preparation of Compound

2-(3-(1H-tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3H)-one

3-(5-Hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile (108 mg, 0.50mmol) and NaN₃ (131 mg, 2.02 mmol) were dissolved in anhydrous DMF (1mL). The reaction mixture was treated with 2 drops of acetic acid. Itwas sealed and then it was heated at 130° C. for 18 hours. The reactionwas cooled to room temperature and gave brownish suspension. It wasfiltered and greenish solid was obtained. The greenish solid wassuspended in 2N HCl followed by second filtration to provide2-(3-(1H-tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3H)-one as a beigesolid (32 mg, 25%); ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.11 (d,J=8 Hz, 1H), 7.97 (d, J=8 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J=8 Hz, 1H);¹³C NMR (100 MHz, DMSO-d₆) δ162.3, 159.1, 158.7, 148.0, 143.4, 133.1,130.4, 128.9, 127.9, 126.5, 125.1.

Example 30 Preparation of Compound

5-(4-Fluorophenyl)-4-hydroxypyridazin-3(2H)-one

5-(4-Fluorophenyl)-4-methoxy-2-(methoxymethyl)pyridazin-3(2H)-one (55mg, 0.21 mmol) was dissolve in anhydrous DCM (10 mL). The reactionmixture was cooled to 0° C. and the 1M in DCM BBr₃ (2.1 mL, 2.1 mmol)was added. It was then allowed to warm to room temperature and stirredfor 24 hours. Then, the solvent was removed under reduced pressure. Thisgave 5-(4-fluorophenyl)-4-methoxypyridazin-3(2H)-one, which was againrecharged with 1M in DCM BBr₃ (2.1 mL, 2.1 mmol). The reaction mixturewas stirred for 24 hours at room temperature. Then, the solvent wasagain removed under reduced pressure. The resulting residue wassuspended with water and filtered. The filtered solid was then flashchromatographed on silica gel eluting with 0-10% MeOH/DCM. This gave5-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one as a white solid (6.2mg, 14%); m.p.274-276° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H),7.76 (s, 1H), 7.58 (J=8 Hz, J=5 Hz, 2H), 7.21-7.17 (m, 2H); ¹³C NMR (100MHz, DMSO-d₆) δ 161.2 (J_(C,F)=243 Hz), 161.9, 154.6, 132.7, 132.4(J_(C,F)=8 Hz), 127.2 (J_(C,F)=4 Hz), 115.8, 114.2 (J_(C,F)=21 Hz); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −114.1

a. Preparation of Compound

4,5-Dichloro-2-(methoxymethyl)pyridazin-3 (2H)-one

4,5-Dichloropyridazin-3(2H)-one (200 mg, 1.21 mmol) and4-Dimethylaminopyridine (15 mg, 0.12 mmol) were dissolved in anhydrousDCM (20 mL). Then, the reaction mixture was cooled to 0° C. and treatedwith NEt₃ (0.29 mL, 1.70 mmol) followed by MOM-Cl (0.110 mL, 1.454mmol). The reaction mixture was allowed to warm to room temperature andstirred for 17 hours. It was then poured into DCM and it was washed withsat. NH₄Cl followed by brine. The organic layer was dried over Na₂SO₄,which was concentrated. The resulting residue was flash chromatographedon silica gel eluting with 0 to 30% EtOAc/Hexane to provide4,5-dichloro-2-(methoxymethyl)pyridazin-3(2H)-one as a white solid (84mg, 33%); m.p.65-67° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 5.41(s, 2H), 3.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.9, 137.0, 136.0,134.9, 82.4, 58.1.

b. Preparation of Compound

5-Chloro-4-methoxy-2-(methoxymethyl)pyridazin-3 (2H)-one

4,5-Dichloro-2-(methoxymethyl)pyridazin-3(2H)-one (84 mg, 0.40 mmol) wasadded to MeOH (10 mL). Then the reaction mixture was cooled to 0° C. Itwas treated with NaOMe (24 mg, 0.442 mmol) and allowed to warm to roomtemperature. The reaction mixture was then stirred for 18 hours at roomtemperature. After the reaction was completed, it was put under thevacuum to remove MeOH. The resulting residue was diluted with EtOAc,which was then washed with sat. NH₄Cl followed by brine. The organiclayer was dried over Na₂SO₄ and then concentrated. The residue was flashchromatographed on silica gel eluting with 0 to 30% EtOAc/Hexane toprovide 5-chloro-4-methoxy-2-(methoxymethyl)pyridazin-3(2H)-one as awhite solid (59 mg, 72%); m.p.101-103° C.; ¹H NMR (400 MHz, CDCl₃) δ7.85 (s, 1H), 5.45 (s, 2H), 4.08 (s, 3H), 3.44 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 159.1, 155.1, 127.1, 116.9, 81.9, 57.9, 57.8.

c. Preparation of Compound

5-(4-Fluorophenyl)-4-methoxy-2-(methoxymethyl)pyridazin-3(2H)-one

5-Chloro-4-methoxy-2-(methoxymethyl)pyridazin-3(2H)-one (58 mg, 0.28mmol), (4-fluorophenyl)boronic acid (140 mg, 0.43 mmol), Pd(PPh₃)₄ (32mg, 0.028 mmol) and Na₂CO₃ (90 mg, 0.85 mmol) were dissolved in amixture of dioxane (9 mL) and water (3 mL). The air was evacuated andreplaced with N₂. Then, the reaction mixture was refluxed for 14 hours.After the reaction was completed, it was cooled to room temperature andit was diluted with EtOAc and washed with sat. NH₄Cl followed by brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo andthe resulting residue was flash chromatographed on silica gel elutingwith 0 to 30% EtOAc/Hexane. This afforded5-(4-fluorophenyl)-4-methoxy-2-(methoxymethyl)pyridazin-3(2H)-one as awhite solid (56 mg, 74%); m.p.123-125° C.; ¹H NMR (400 MHz, CDCl₃) δ7.95 (s, 1H), 7.53 (dd, J=9 Hz, J=6 Hz, 2H), 7.11-7.07 (m, 2H), 5.48 (s,2H), 3.93 (s, 3H), 3.49 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6(J_(C,F)=247 Hz), 161.6, 154.8, 132.3 (J_(C,F)=8 Hz), 128.5, 125.7,120.7, 112.9 (J_(C,F)=22 Hz), 81.6, 57.9, 57.3; ¹⁹F NMR (376 MHz, CDCl₃)δ −112.6.

Example 31 Preparation of Compound

6-(4-Fluorophenyl)-4-hydroxypyridazin-3(2H)-one

6-(4-Fluorophenyl)-4-methoxypyridazin-3(2H)-one (16 mg, 0.074 mmol) wasdissolve in anhydrous DCM (5 mL). The reaction mixture was cooled to 0°C. and the 1M in DCM BBr₃ (0.74 mL, 0.74 mmol) was added. It was thenallowed to warm to room temperature and stirred for 36 hours. Then, thesolvent was removed under reduced pressure. The resulting residue wassuspended in water. It was filtered and the solid was collected anddried under vacuum to provide6-(4-fluorophenyl)-4-hydroxypyridazin-3(2H)-one as a white solid (5 mg,35%); m.p.281-283° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.10 (bs, 1H), 11.02(bs, 1H), 7.87 (dd, J=9 Hz, J=5 Hz, 2H), 7.30-7.26 (m, 2H), 7.19 (s,1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.6 (J_(C,F)=245 Hz), 157.6, 155.4,145.2, 132.0 (J_(C,F)=3 Hz), 128.0 (J_(C,F)=9 Hz), 115.6 (J_(C,F)=22Hz), 106.0; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.0.

a. Preparation of Compound

6-Chloro-3,4-dimethoxypyridazine

3,4,6-Trichloropyridazine (200 mg, 1.09 mmol) was added to MeOH (15 mL).Then the reaction mixture was cooled to 0° C. It was treated with NaOMe(117 mg, 2.17 mmol) and allowed to warm to room temperature. Thereaction mixture was then stirred for 10 hours at room temperature.After the reaction was completed, it was put under the vacuum to removeMeOH. The resulting residue was diluted with EtOAc, which was thenwashed with sat. NH₄Cl followed by brine. The organic layer was driedover Na₂SO₄ and then concentrated. The residue was flash chromatographedon silica gel eluting with 0 to 30% EtOAc/Hexane to provide4-chloro-5,6-dimethoxypyrimidine as a white solid (101 mg, 53%);m.p.117-119° C.; ¹H NMR (400 MHz, CDCl₃) δ 6.71 (s, 1H), 4.08 (s, 3H),3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.9, 151.1, 149.8, 108.4,56.2, 55.3.

b. Preparation of Compound

6-(4-Fluorophenyl)-3,4-dimethoxypyridazine

6-Chloro-3,4-dimethoxypyridazine (101 mg, 0.58 mmol),(4-fluorophenyl)boronic acid (122 mg, 0.87 mmol), Pd(PPh₃)₄ (67 mg, 0.06mmol) and Na₂CO₃ (184 mg, 1.74 mmol) were dissolved in a mixture ofdioxane (15 mL) and water (5 mL). The air was evacuated and replacedwith N₂. Then, the reaction mixture was refluxed for 3 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure and the resulting residue was flash chromatographed on silicagel eluting with 0 to 20% EtOAc/Hexane. This afforded6-(4-fluorophenyl)-3,4-dimethoxypyridazine as a white solid (109 mg,80%); m.p.103-105° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd, J=9 Hz, J=5Hz, 2H), 7.10-7.06 (m, 2H), 7.00 (s, 1H), 4.14 (s, 3H), 3.93 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 163.7 (J_(C,F)=247 Hz), 156.5, 155.7, 148.9,132.9 (J_(C,F)=3 Hz), 128.5 (J_(C,F)=9 Hz), 115.8 (J_(C,F)=21 Hz),104.7, 55.7, 55.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −112.2.

c. Preparation of Compound

6-(4-Fluorophenyl)-4-methoxypyridazin-3(2H)-one

6-(4-Fluorophenyl)-3,4-dimethoxypyridazine (122 mg 0.52 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 11 hours. It was then cooled to roomtemperature. The reaction mixture was diluted with EtOAc and washed withsat. NaHCO₃ followed by brine. The organic layer was dried over Na₂SO₄and concentrated. The resulting residue was flash chromatographed onsilica gel eluting with 0 to 10% MeOH/DCM to give6-(4-fluorophenyl)-4-methoxypyridazin-3(2H)-one as a white solid (41 mg,36%); m.p.211-213° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (br s, 1H),7.96 (dd, J=9 Hz, J=6 Hz, 2H), 7.34-7.29 (m, 2H), 7.28 (s, 1H), 3.92 (s,3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.7 (J_(C,F)=245 Hz), 156.2, 155.7,144.3, 132.0 (J_(C,F)=3 Hz), 128.2 (J_(C,F)=8 Hz), 115.6 (J_(C,F)=22Hz), 104.4, 56.2; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −112.9.

Example 32 Preparation of Compound

4-(5-Hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

4-(5-Methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (109 mg, 0.48mmol) was dissolved in anhydrous DCM (5 mL). The reaction mixture wascooled to 0° C. and the 1M in DCM BBr₃ (4.8 mL, 4.8 mmol) was added. Itwas then allowed to warm to room temperature and stirred for 20 hours.Then, the solvent was removed under reduced pressure. The resultingresidue was suspended in water. It was filtered and the solid wascollected. The solid was dry loaded on silica gel and flashchromatographed eluting with 0 to 10% MeOH/DCM. This afforded4-(5-hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile as a whitesolid (75 mg, 73%); m.p.305-307° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.29(s, 1H), 11.15 (bs, 1H), 8.03 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H),7.29 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.7, 154.6, 144.4, 139.8,132.7, 126.5, 118.6, 111.4, 106.0

a. Preparation of Compound

4-(5,6-Dimethoxypyridazin-3-yl)benzonitrile

6-Chloro-3,4-dimethoxypyridazine (298 mg, 1.71 mmol),(4-cyanophenyl)boronic acid (376 mg, 2.56 mmol), Pd(PPh₃)₄ (198 mg, 0.17mmol) and Na₂CO₃ (543 mg, 5.12 mmol) were dissolved in a mixture ofdioxane (15 mL) and water (5 mL). The air was evacuated and replacedwith N₂. Then, the reaction mixture was refluxed for 15 hours. After thereaction was completed, it was cooled to room temperature and it wasdiluted with EtOAc and washed with sat. NH₄Cl followed by brine. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure and the resulting residue was flash chromatographed on silicagel eluting with 0 to 30% EtOAc/Hexane. This afforded4-(5,6-dimethoxypyridazin-3-yl)benzonitrile as a white solid (130 mg,31%); m.p.187-189° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=8 Hz, 2H),7.77 (d, J=8 Hz, 2H), 7.14 (s, 1H), 4.23 (s, 3H), 4.03 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 157.1, 154.7, 149.1, 140.9, 132.6, 127.3, 118.5,113.0, 104.9, 55.9, 55.3.

b. Preparation of Compound

4-(5-Methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile

4-(5,6-Dimethoxypyridazin-3-yl)benzonitrile (125 mg, 0.52 mmol) wasdissolved in a mixture of 2N HCl (5 mL) and dioxane (5 mL). The reactionmixture was then refluxed for 4 hours. It was then cooled to roomtemperature and then put under reduced pressure. The resulting residuewas suspended in water and filtered. The product4-(5-methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile was collectedas a white solid (82 mg, 70%); m.p.271-273° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.97 (bs, 1H), 8.02 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H),6.62 (s, 1H), 3.96 (s, 3H).

Example 33 Preparation of Compound

6-(4-(1H-Tetrazol-5-yl)phenyl)-4-hydroxypyridazin-3(2H)-one

4-(5-Methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile (56 mg, 0.26mmol) and NaN₃ (69 mg, 1.06 mmol) were dissolved in anhydrous DMF (1mL). The reaction mixture was treated with 2 drops of acetic acid. Itwas sealed and then it was heated at 130° C. for 21 hours. The reactionwas cooled to room temperature and gave brownish suspension. Thesuspension was filtered and gave a white solid, which was treated with2N HCl and filtered again. This afforded6-(4-(1H-tetrazol-5-yl)phenyl)-4-hydroxypyridazin-3(2H)-one as a whitesolid (33 mg, 48%); ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.09 (d,J=8 Hz, 2H), 7.95 (d, J=7 Hz, 2H), 7.25 (s, 1H).

Example 34 Preparation of Compound

5-Cyclohexyl-3-hydroxypyridin-2(1H)-one

To a solution of 2-ethoxy-3-methoxy-5-cyclohexylpyridinepyridine (30 mg,0.13 mmol) in CH₂Cl₂ (2.0 ml) under nitrogen, was added boron tribromide(0.5 ml of a 1.0 M solution in CH₂Cl₂). After addition was completed,the reaction mixture was stirred for 16 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford theproduct (22 mg) as solid, yield: 90%. ¹H NMR (300 MHz, DMSO-d₆) δ: 6.65(s, 1H), 6.55 (s, 1H), 2.2 (m, 1H), 1.7 (m, 5H), 1.35 (m, 5H).

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-2-ethoxy-3-methoxypyridine (279 mg, 1.0 mmol),1-cyclohexenyl boronic acid pinacole ester (250 mg, 1.2 mmol), Pd(PPh₃)₄(139 mg, 0.12 mmol) and K₂CO₃ (277 mg, 2.0 mmol) in 1,4-dioxane (3.0 ml)and H₂O (1.0 ml) was degassed for 30 min. This mixture was heated to100° C. and stirred for 16 h. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated. The resulting residue was purified by ISCO flashchromatography using 10% EtOAc in hexane to give 551 mg (97%) of thedesired product. ¹H NMR (300 MHz, CDCl₃) δ: 7.7 (s, 1H), 7.04 (s, 1H),6.0 (m, 1H), 4.4 (qt, 2H), 3.84 (s, 3H), 2.36 (m, 2H), 2.18 (m, 2H),1.78 (m, 2H), 1.7 (m, 2H), 1.4 (t, 3H).

b. Preparation of Compound

To a solution of 5-cyclohexenyl-2-ethoxy-3-methoxypyridine (200 mg, 0.86mmol) in methanol (10 ml) was added catalytic amount of Pd/C. Themixture was evacuated three times and then was charged with hydrogen ina balloon. The reaction mixture was stirred at room temperature for 16 hafter which the catalyst was filtered off and the solvent was removed toafford the crude product. The crude product was purified by ISCO flashchromatography using 5% EtOAc in hexane to give 172 mg (85%) of thedesired product. ¹H NMR (300 MHz, CDCl₃) δ: 7.48 (s, 1H), 6.84 (s, 1H),4.36 (qt, 2H), 3.79 (s, 3H), 2.4 (m, 1H), 1.79 (m, 5H), 1.39-1.31 (m,8H).

Example 35 Preparation of Compound

5-[3-(1H-Tetrazol-5-yl)phenyl]-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added3-(5,6-dihydroxypyridin-3-yl)benzonitrile (65 mg, 0.31 mmol), DMF (2.0ml), NaN₃ (80 mg, 1.2 mmol) followed by few drops of AcOH. The resultingmixture was heated to 120° C. overnight. After the completion of thereaction, the solvent was removed under vacuum. Addition of 1N HCl andstirring produced a solid which was filtered to give the pure product(13 mg, 17% yield). ¹H NMR (300 MHz, DMSO-d₆) δ: 9.35 (bs, 1H), 8.18 (s,1H), 7.97 (m, 1H), 7.77 (m, 1H), 7.63 (m, 1H), 7.36 (m, 1H), 7.21 (m,1H).

The requisite intermediates were prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (217 mg, 1.0 mmol),3-cyanophenylboronic acid (220 mg, 1.5 mmol), Pd(PPh₃)₄ (173 mg, 0.15mmol) and K₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (5.0 ml) and H₂O (1.5ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 20%EtOAc in hexane to give 190 mg (79% yield) desired product as whitesolid. ¹H NMR (300 MHz, CDCl₃) δ: 7.91 (d, J=2.1 Hz, 1H), 7.79-7.73 (m,2H), 7.61-7.53 (m, 2H), 7.17 (d, J=2.1 Hz, 1H), 4.05 (s, 3H), 3.94 (s,3H).

b. Preparation of Compound

5-(m-Cyanophenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5(3-cyanophenyl)pyridine (40 mg, 0.167mmol) in DCM (4.0 ml) under nitrogen, boron tribromide (0.8 ml of 1.0 Msolution in CH₂Cl₂) was added. After addition was completed, thereaction mixture was stirred at room temperature overnight. The solventwas removed from the reaction mixture and the resulting solid waspurified in ISCO using 10% MeOH in DCM to furnish the pure product (20mg) yield: 53%. ¹H NMR (300 MHz, Acetone d₆) δ: LC/MS: 213 (M+H).

Example 36 Preparation of Compound

3-(5-Hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

To a solution of 2,3-dimethoxy-5(3-benzoate)pyridine (110 mg, 0.4 mmol)in DCM (2.0 ml) under nitrogen, boron tribromide (1.5 ml of 1.0 Msolution in CH₂Cl₂) was added. After addition was completed, thereaction mixture was stirred at room temperature overnight. The solventwas removed from the reaction mixture and the resulting solid waspurified in ISCO using 10% MeOH in DCM to furnish the pure product (20mg) yield: 53%. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.30 (s, 1H), 8.0 (s, 1H),7.86-7.78 (m, 2H), 7.52 (m, 1H), 7.27 (s, 1H), 7.11 (d, 1H).

The requisite intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (217 mg, 1.0 mmol),3-carbomethoxyphenylboronic acid (270 mg, 1.5 mmol), Pd(PPh₃)₄ (138 mg,0.12 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (5.0 ml) and H₂O(1.5 ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 10%EtOAc in hexane to give 190 mg (79% yield) desired product. ¹H NMR (300MHz, CDCl₃) δ: 8.21 (s, 1H), 8.04-7.97 (m, 2H), 7.75 (d, J=9.0 Hz, 1H),7.53 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 4.07 (s, 3H), 3.97 (s, 6H).

Example 37 Preparation of Compound

5-(3-Fluorophenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5-(3-fluorophenyl)pyridine (40 mg, 0.17mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide (0.8ml of a 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 16 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford thecrude product which was purified in ISCO using 5% MeOH in DCM to furnishthe pure product (10 mg), yield: 28%. ¹H NMR (300 MHz, DMSO-d₆) δ: 9.29(s, 1H), 7.43-7.34 (m, 4H), 7.15 (m, 2H), 5.78 (s, 1H).

The requisite intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 2,3-dimethoxypyridine (120 mg, 0.55 mmol),3-fluorophenylboronic acid (115 mg, 0.83 mmol), Pd(PPh₃)₄ (92 mg, 0.08mmol) and K₂CO₃ (151 mg, 1.1 mmol) in 1,4-dioxane (3.0 ml) and H₂O (1.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 20%EtOAc in hexane to give 110 mg (83%) of the desired product. ¹H NMR (300MHz, CDCl₃) δ: 7.96 (s, 1H), 7.47 (m, 1H), 7.35-7.30 (m, 1H), 7.27-7.24(m, 2H), 7.10-7.04 (m, 1H), 4.09 (s, 3H), 3.97 (s, 3H).

Example 38 Preparation of Compound

4-(5-Hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

To a solution of 2,3-dimethoxy-5(4-benzoate)pyridine (80 mg, 0.29 mmol)in DCM (3.0 ml) and toluene (3.0 ml) under nitrogen, boron tribromide(1.8 ml of 1.0 M solution in CH₂Cl₂) was added. After addition wascompleted, the reaction mixture was refluxed for 16 h. The solvent wasremoved from the reaction mixture and the resulting solid was purifiedin ISCO using 10% MeOH in DCM with 1% acetic acid to furnish the pureproduct (15 mg) yield: 21%. ¹H NMR (300 MHz, DMSO-d₆) δ: 10.65 (bs, 1H),8.10 (s, 1H), 8.00 (m, 2H), 7.84 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.45(d, J=8.1 Hz, 1H).

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (217 mg, 1.0 mmol),4-carbomethoxyphenylboronic acid (270 mg, 1.5 mmol), Pd(PPh₃)₄ (138 mg,0.12 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (5.0 ml) and H₂O(1.5 ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 10%EtOAc in hexane to give 136 mg (50% yield) desired product. ¹H NMR (300MHz, CDCl₃) &: 8.12 (d, 2H), 8.0 (d, 1H), 7.6 (d, 2H), 4.08 (s, 3H),3.96 (s, 3H), 3.95 (s, 3H).

Example 39 Preparation of Compound

3,3′-(5-Hydroxy-6-oxo-1,6-dihydropyridine-2,3-diyl)dibenzoic acid

To a solution of 2,3-dimethoxy-5,6-(3-methylbenzoate)pyridine (96 mg,0.236 mmol) in DCM (3.0 ml) and toluene (3.0 ml) under nitrogen, borontribromide (1.5 ml of 1.0 M solution in CH₂Cl₂) was added. Afteraddition was completed, the reaction mixture was stirred at 80° C.overnight. The solvent was removed from the reaction mixture and theresulting solid was purified in ISCO using 10% MeOH in DCM with 1%acetic acid to furnish the pure product (35 mg), yield: 42%. ¹H NMR (300MHz, DMSO-d₆) δ: 7.83 (m, 1H), 7.73 (m, 2H), 7.59 (m, 1H), 7.4-7.24 (m,4H), 6.87 (s, 1H).

The requisite intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (296 mg, 1.0 mmol),3-carbomethoxyphenylboronic acid (270 mg, 1.5 mmol), Pd(PPh₃)₄ (173 mg,0.15 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (3.0 ml) and H₂O(1.0 ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 20%EtOAc in hexane to give 106 mg (26%) of the desired product. ¹H NMR (300MHz, CDCl₃) δ: 8.13 (s, 1H), 7.99 (s, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.88(d, J=7.8 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.31-7.20 (m, 3H), 7.10 (s,1H), 4.13 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H).

Example 40 Preparation of Compound

5-Phenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5-phenylpyridine (100 mg, 0.465 mmol) inCH₂Cl₂ (3.0 ml) under nitrogen, boron tribromide was added (1.0 ml of1.0 M solution in CH₂Cl₂). After addition was completed, the reactionmixture was stirred for 16 h at room temperature. Dichloromethane wasremoved and the reaction mixture was diluted with ethyl acetate. Thesolution was washed with NaHCO₃ and brine. The organic phase was thendried and evaporated under reduced pressure to afford the crude productwhich was purified in ISCO using 10% MeOH in DCM to furnish the pureproduct (21 mg) as white solid, yield: 24%. mp 175-177° C.; ¹H NMR (300MHz, DMSO-d₆) δ: 9.33 (bs, 1H), 7.62-7.38 (m, 5H), 7.30 (s, 1H), 7.20(s, 1H). ¹³C NMR (75 MHz, DMSO d₆) δ: 172.5, 158.3, 147.9, 137.3, 129.6,126.0, 121.9, 115.6, 107.7. HRMS Calcd for C₁H9NO₂ (M+H)⁺ 188.0706.Found 188.0708.

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (100 mg, 0.46 mmol),phenylboronic acid (84 mg, 0.69 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol) andK₂CO₃ (125 mg, 0.92 mmol) in 1,4-dioxane (3.0 ml) and H₂O (1.0 ml) wasdegassed for 30 min. This mixture was heated to 100° C. and stirred for16 h. The reaction mixture was cooled to room temperature andpartitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl (1×).The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using DCM togive 100 mg (99.9%) desired product. ¹H NMR (300 MHz, CDCl₃) δ: 7.97 (s,1H), 7.53-7.36 (m, 5H), 7.24 (s, 1H), 4.06 (s, 3H), 3.92 (s, 3H). ¹³CNMR (75 MHz, CDCl₃) δ: 176.1, 153.8, 144.0, 138.0, 134.9, 130.8, 129.6,128.9, 127.4, 126.8, 116.4, 56.2, 54.2.

Example 41 Preparation of Compound

5-(4-Cyanophenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5(4-cyanophenyl)pyridine (100 mg, 0.417mmol) in toluene (3.0 ml) under nitrogen, boron tribromide (1.2 ml of1.0 M solution in CH₂Cl₂) was added. After addition was completed, thereaction mixture was heated to 100° C. in a sealed tube for 2 h and thenat room temperature overnight. The solvent was removed from the reactionmixture and the resulting solid was purified in ISCO using 10% MeOH inDCM to furnish the pure product (86 mg) yield: 60%. ¹H NMR (300 MHz,Acetone d₆) δ: 7.67 (s, 4H), 7.36 (s, 1H), 7.10 (s, 1H). HRMS Calcd forC₁₂H₈N₂O₂ (M+H)⁺ 212.0580. Found 212.0578.

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (570 mg, 2.63 mmol),4-cyanophenylboronic acid (578 mg, 3.94 mmol), Pd(PPh₃)₄ (311 mg, 0.27mmol) and K₂CO₃ (717 mg, 5.2 mmol) in 1,4-dioxane (6.0 ml) and H₂O (1.5ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 20%EtOAc in hexane to give 495 mg (78% yield) desired product. ¹H NMR (300MHz, CDCl₃) δ: 7.74 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz,2H), 7.0 (s, 1H), 3.84 (s, 3H), 3.73 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ:176.2, 154.7, 144.3, 142.6, 135.4, 132.7, 128.7, 127.3, 118.8, 115.7,110.9, 55.8, 54.0.

Example 42 Preparation of Compound

5-[4-(1H-Tetrazol-5-yl)phenyl]-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added4-(5,6-dihydroxypyridin-3-yl)benzonitrile (86 mg, 0.40 mmol), DMF (3.0ml), NaN₃ (104 mg, 1.6 mmol) followed by AcOH (1.0 ml). The resultingmixture was heated to 120° C. overnight. After the completion of thereaction, the solvent was removed under vacuum. Addition of 1N HCl andstirring produced a solid which was filtered to give the pure product(35 mg, 34% yield). ¹H NMR (300 MHz, DMSO-d₆) δ: 7.96 (m, 3H), 7.53 (d,J=9.0 Hz, 2H), 7.22 (s, 1H), 7.16 (s, 1H). HRMS Calcd for C₁₂H9N₅O₂(M+H)⁺ 256.0929. Found 256.0827.

Example 43 Preparation of Compound

6-(4-Cyanophenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2-ethoxy-3-methoxy-6-(4-cyanophenyl)pyridine (150 mg,0.59 mmol) in CH₂Cl₂ (5.0 ml) under nitrogen, was added boron tribromide(2.0 ml, 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 16 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford thecrude product which was purified in ISCO using 10% MeOH in DCM tofurnish the pure product (90 mg) as tan solid, yield: 72%. mp 161-163°C.; ¹H NMR (300 MHz, DMSO-d₆) δ: 7.88 (s, 4H), 6.85 (d, J=7.5 Hz, 1H),6.68 (d, J=7.5 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ: 172.5, 159.1,148.0, 138.8, 134.6, 133.3, 127.3, 119.4, 116.9, 111.1, 107.6. HRMSCalcd for C₁₂8₉N₂O₂ (M+H)⁺ 213.0659. Found 213.0651.

The requisite intermediate was prepared as follows.

a. Preparation of Compound

A mixture of 6-iodo-2-ethoxy-3-methoxypyridine (150 mg, 0.894 mmol),4-cyanophenylboronic acid (197 mg, 1.34 mmol), Pd(PPh₃)₄ (155 mg, 0.136mmol) and K₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (3.0 ml) and H₂O (1.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 20%EtOAc in hexane to give 185 mg (82% yield) desired product. ¹H NMR (300MHz, CDCl₃) δ: 8.07 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.37 (d,J=8.4 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.59 (qt, 2H), 3.93 (s, 3H), 1.51(t, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 172.2, 153.5, 144.5, 143.0, 142.5,132.4, 126.3, 119.1, 117.5, 113.7, 110.9, 62.1, 55.9, 14.6.

Example 44 Preparation of Compound

6-[4-(1H-tetrazol-5-yl)phenyl]-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added6-(4-cyanophenyl-3-hydroxypyridin-2(1H)-one (50 mg, 0.235 mmol), DMF(2.0 ml), NaN₃ (61 mg, 0.94 mmol) followed by AcOH (1.0 ml). Theresulting mixture was heated to 120° C. overnight. After the completionof the reaction, the solvent was removed under vacuum. Addition of 1NHCl and stirring produced a solid which was filtered to give the pureproduct (51 mg, 85% yield). ¹H NMR (300 MHz, DMSO-d₆) δ: 8.07 (d, 2H),7.83 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.4 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H),6.59 (d, J=7.5 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ: 172.5, 159.4,135.5, 127.6, 127.2, 114.3, 107.6. HRMS Calcd for C₁₂H9N₅O₂ (M+H)⁺256.0829. Found 256.0820.

Example 45 Preparation of Compound

5,6-bis(4-Cyanophenyl)-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5,6-bis(4-cyanophenyl)pyridine (50 mg,0.146 mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added borontribromide (1.0 M solution in CH₂Cl₂) (1.5 ml). After addition wascompleted, the reaction mixture was stirred for 16 h at roomtemperature. Dichloromethane was removed from the reaction mixturefollowed by addition of HCl (3N). The resulting solid was filtered,which was redissolved in CH₂Cl₂ and washed with NaHCO₃ and brine, driedusing anhydrous sodium sulfate and evaporated under reduced pressure toafford a solid (15 mg), yield: 33%. mp 159-162° C.; 1H NMR (300 MHz,MeOD-d₄) δ: 7.62 (m 4H), 7.3 (m, 4H), 7.03 (s, 1H). HRMS Calcd forC₁₉H₁₁N₃O₂ (M+H)⁺ 314.0924. Found 314.0920.

The requisite intermediate was prepared as follows.

a. Preparation of Compound

The mixture of 5,6-dibromo-2,3-dimethoxypyridine (100 mg, 0.338 mmol),4-cyanophenylboronic acid (102 mg, 0.7 mmol), Pd(PPh₃)₄ (58 mg, 0.05mmol) and K₂CO₃ (136 mg, 1.0 mmol) in 1,4-dioxane (3.0 ml) and H₂O (1.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 30%EtOAc in hexane to give 56 mg of the desired product, yield: 49%. ¹H NMR(300 MHz, CDCl₃) δ: 7.56 (d, J=8.1 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.36(d, J=8.4 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.0 (s, 1H), 4.05 (s, 3H),3.91 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ: 172.3, 153.7, 144.3, 144.0,143.6, 142.0, 132.4, 131.7, 130.5, 130.4, 128.1, 119.6, 118.7, 118.5,111.2, 111.1, 58.2, 56.2.

Example 46 Preparation of Compound

5,6-bis[4-(1H-Tetrazol-5-yl)phenyl]-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added5,6-bis(4-cyanophenyl)-3-hydroxypyridin-2(1H)-one (100 mg, 0.319 mmol),DMF (2.0 ml), NaN₃ (61 mg, 0.94 mmol) followed by AcOH (1.0 ml). Theresulting mixture was heated to 120° C. overnight. After completion ofthe reaction, the solvent was removed under vacuum. Addition of 1N HCland stirring produced a solid which was filtered to give the pureproduct (45 mg, 35% yield). mp 180-182° C.; ¹H NMR (300 MHz, DMSO-d₆) δ:7.96 (bs, 2H), 7.85-7.77 (m, 4H), 7.18 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 6.84 (s, 1H). HRMS Calcd for C₁₉H₁₃N₉O₂ (M+H)⁺400.1265. Found400.1262.

Example 47 Preparation of Compound

5-(4-Fluorophenyl)-6-(4-cyanophenyl)-3-hydroxypyridin-2(1H)-one

To a solution of5-(4-fluorophenyl)-6-(4-cyanophenyl)-2,3-dimethoxypyridine (240 mg, 0.72mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide (2.0ml of a 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 16 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford thecrude product which was purified in ISCO using 5% MeOH in DCM to furnishthe pure product (183 mg) as off-white solid, yield: 83%. mp 255-258°C.; ¹H NMR (300 MHz, DMSO-d₆) δ: ¹H NMR (300 MHz, DMSO-d₆) δ: 7.75 (d,J=8.1 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.07 (d, J=7.2 Hz, 4H), 6.82 (s,1H). ¹³C NMR (75 MHz, DMSO-d₆) δ: 172.5, 147.0, 132.7, 132.5, 132.2,132.1, 131.6, 119.2, 116.1, 115.7, 107.6. HRMS Calcd for C₁₈H₁₁FN₂O₂(M+H)⁺ 307.0877. Found 307.0844.

The requisite intermediates were prepared as follows.

a. Preparation of Compound

A mixture of 6-bromo-2,3-dimethoxypyridine (434 mg, 2.0 mmol),4-cyanophenylboronic acid (440 mg, 3.0 mmol), Pd(PPh₃)₄ (346 mg, 0.3mmol) and K₂CO₃ (552 mg, 4.0 mmol) in 1,4-dioxane (3 ml) and H₂O (1.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 25%EtOAc in hexane to give 200 mg desired product. ¹H NMR (300 MHz, CDCl₃)δ: 8.04 (d, J=8.7 Hz, 2H), 7.6 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.1 Hz,1H), 7.09 (d, J=8.1 Hz, 1H), 4.09 (s, 3H), 3.90 (s, 3H).

b. Preparation of Compound

To a mixture of 2,3-dimethoxy-6-(4-cyanophenyl)pyridine (210 mg, 0.875mmol) in acetic acid (3.0 ml) was added sodium acetate (217 mg, 1.6mmol). The reaction mixture was cooled to 0° C. and Br₂ (0.045 ml) inacetic acid (1.0 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 12 h. To this mixture 25% NaOH was addedat 0° C. until pH 6 and then extracted with DCM three times. Organiclayer wad dried, concentrated under reduced pressure and purified byISCO using 20% EtOAC in hexane to afford pure product 360 mg (91%yield). ¹H NMR (300 MHz, CDCl₃) δ: 7.51 (d, J=8.7 Hz, 2H), 7.55 (d,J=8.4 Hz, 2H), 6.97 (s, 1H), 4.07 (s, 3H), 3.89 (s, 3H).

c. Preparation of Compound

A mixture of 5-bromo-6-(4-cyanophenyl)-2,3-dimethoxypyridine (360 mg,1.13 mmol), 4-fluorophenylboronic acid (237 mg, 1.69 mmol), Pd(PPh₃)₄(173 mg, 0.15 mmol) and K₂CO₃ (307 mg, 2.26 mmol) in 1,4-dioxane (3 ml)and H₂O (1.5 ml) was degassed for 30 min. This mixture was heated to100° C. and stirred for 16 h. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated. The resulting residue was purified by ISCO flashchromatography using 25% EtOAc in hexane to give 340 mg (90% yield) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ: 7.49-7.40 (m, 4H),7.13-7.09 (m, 2H), 7.02-6.95 (m, 3H), 4.07 (s, 3H), 3.92 (s, 3H). ¹³CNMR (75 MHz, CDCl₃) δ: 163.8, 160.5, 153.1, 144.17, 143.76, 141.56,135.47, 135.42, 132.86, 131.54, 131.31, 131.20, 130.50, 129.05, 127.94,120.16, 118.96, 115.96, 115.57, 110.58, 56.01, 53.88.

Example 48 Preparation of Compound

5-(4-Cyanophenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

To a solution of5-(4-cyanophenyl)-6-(4-fluorophenyl)-2,3-dimethoxypyridine (150 mg, 0.45mmol) in CH₂Cl₂ (4.0 ml) under nitrogen, was added boron tribromide (2.0ml of a 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 20 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford thecrude product which was purified in ISCO using 5% MeOH in DCM to furnishthe pure product (85 mg) as white solid, yield: 62%. mp 255-257° C.; ¹HNMR (300 MHz, DMSO-d₆) δ: 9.39 (bs, 1H), 7.60 (d, J=8.1 Hz, 2H),7.14-7.03 (m, 6H), 6.77 (s, 1H). HRMS Calcd for C₁₈H₁₁FN₂O₂ (M+H)⁺307.0877. Found 307.0870.

The requisite intermediates were prepared as follows.

a. Preparation of Compound

To a solution of 2,3-dimethoxy-5-(4-cyanophenyl)pyridine (350 mg, 1.46mmol) in acetic acid (8.0 ml) was added sodium acetate (402 mg, 2.9mmol). The reaction mixture was cooled to 0° C. and Br₂ (238 mg) inacetic acid (1.0 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 16 h. To this mixture 25% NaOH was addedat 0° C. until pH 6 and then extracted with dichloromethane three times.Organic layer wad dried, concentrated under reduced pressure andpurified by ISCO using 100% DCM to afford pure product 310 mg (66%yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ: 7.70 (d, J=8.1 Hz, 2H),7.54 (d, J=8.1 Hz, 2H), 6.99 (s, 1H). ¹³C NMR (75 MHz, CDCl₃) δ: 172.5,153.4, 143.9, 132.3, 130.7, 120.7, 118.8, 111.9, 56.5, 54.4.

b. Preparation of Compound

A mixture of 6-bromo-5-(4-cyanophenyl)-2,3-dimethoxypyridine (150 mg,0.47 mmol), 4-fluorophenylboronic acid (99 mg, 0.70 mmol), Pd(PPh₃)₄ (70mg, 0.06 mmol) and K₂CO₃ (129 mg, 0.94 mmol) in 1,4-dioxane (3.0 ml) andH₂O (1.0 ml) was degassed for 30 min. This mixture was heated to 100° C.and stirred for 16 h. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated. The resulting residue was purified by ISCO flashchromatography using 25% EtOAc in hexane to give 150 mg (95% yield)desired product. ¹H NMR (300 MHz, CDCl₃) δ: 7.51 (m, 2H), 7.35-7.33 (m,2H), 7.27-7.22 (m, 2H), 6.99 (s, 1H), 6.89 (t, J=8.7 Hz, 2H), 4.08 (s,3H), 3.92 (s, 3H).

Example 49 Preparation of Compound

5-[4-(1H-Tetrazol-5-yl)phenyl]-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added5-(4-cyanophenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (45 mg,0.141 mmol), DMF (2.0 ml), NaN₃ (38 mg, 0.56 mmol) followed by AcOH (0.1ml). The resulting mixture was heated to 120° C. for 4 h. After thecompletion of the reaction, the solvent was removed under reducedpressure. Addition of 3N HCl and stirring produced a solid which wasfiltered to give the pure product (15 mg, 31% yield). mp 185-188° C.; ¹HNMR (300 MHz, DMSO-d₆) δ: 9.4 (bs, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.20 (d,J=7.8 Hz, 4H), 7.10 (m, 2H), 6.86 (s, 1H). HRMS Calcd for C₁₈H₁₂FN₅O₂(M+H)⁺ 350.1048. Found 350.1057.

Example 50 Preparation of Compound

5,6-bis(4-Fluorophenyl)-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5,6-bis(4-fluorophenyl)pyridine (100 mg,0.3 mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide(1.0 M solution in CH₂Cl₂) (1.5 ml). After addition was completed, thereaction mixture was stirred for 16 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered, which wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine, dried usinganhydrous sodium sulfate and evaporated under reduced pressure to afforda solid (80 mg), yield: 87%. mp 152-157° C.; ¹H NMR (300 MHz, DMSO-d₆)δ: 7.66 (m, 2H), 7.6 (m, 2H), 7.46 (m, 2H), 7.20 (d, J=6.0 Hz, 2H), 7.08(m, 1H), 6.7 (d, 1H), 6.28 (d, 1H). HRMS Calcd for C₁₇H₁₁F₂NO₂ (M+H)⁺300.0831. Found 300.0830.

The requisite intermediate was prepared as follows

a. Preparation of Compound

The mixture of 5,6-dibromo-2,3-dimethoxypyridine (260 mg, 0.87 mmol),4-fluorophenylboronic acid (367 mg, 3.0 mmol), Pd(PPh₃)₄ (303 mg, 0.26mmol) and K₂CO₃ (414 mg, 3.0 mmol) in 1,4-dioxane (4.0 ml) and H₂O (1.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 10%EtOAc in hexane to give 210 mg of the desired product, yield: 73%. ¹HNMR (300 MHz, CDCl₃) δ: 7.35 (m, 2H), 7.20 (m, 2H), 7.20 (m, 2H), 7.17(m, 2H), 7.04-6.98 (m, 4H), 4.18 (s, 3H), 3.01 (s, 3H). LC/MS: 328.205(M+H).

Example 51 Preparation of Compound

5,6-Diphenyl-3-hydroxypyridin-2(1H)-one

To a solution of 2,3-dimethoxy-5,6-diphenylpyridine (130 mg, 0.45 mmol)in CH₂Cl₂ (6.0 ml) under nitrogen, was added boron tribromide (2.0 ml ofa 1.0 M solution in CH₂Cl₂). After addition was completed, the reactionmixture was stirred for 16 h at room temperature. Dichloromethane wasremoved from the reaction mixture followed by addition of HCl (3N). Theresulting solid was filtered. The solid was redissolved in CH₂Cl₂ andwashed with NaHCO₃ and brine. The organic phase was then dried andevaporated under reduced pressure to afford a solid (60 mg), yield: 55%.¹H NMR (300 MHz, DMSO-d₆) δ: 11.89, 9.31, 7.58 (m, 6H), 7.23 (t, 1H),7.15 (m, 1H), 7.07 (t, 1H), 6.7 (d, J=7.2 Hz, 1H). ¹³C NMR (75 MHz,DMSO-d₆) δ: 172.5, 158.7, 146.9, 139.2, 134.7, 130.6, 130.1, 128.8,128.7, 127.1, 119.3, 107.7. HRMS Calcd for C₁₇H₁₃NO₂ (M+H)⁺ 264.1019.Found 264.1020. mp 249-255° C.

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (150 mg, 0.5 mmol,phenylboronic acid (242 mg, 2.0 mmol), Pd(PPh₃)₄ (231 mg, 0.2 mmol) andK₂CO₃ (276 mg, 2.0 mmol) in 1,4-dioxane (5.0 ml) and H₂O (1.5 ml) wasdegassed for 30 min. This mixture was heated to 100° C. and stirred for16 h. The reaction mixture was cooled to room temperature andpartitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl (1×).The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 10%EtOAc in hexane to give 130 mg of the desired product, yield: 89%. ¹HNMR (300 MHz, CDCl₃) δ: 7.4 (m, 2H), 7.29 (m, 3H), 7.24-7.21 (m, 5H),7.12 (s, 1H), 4.15 (s, 3H), 3.96 (s, 3H). LC/MS: 292.23 (M+H).

Example 52 Preparation of Compound

4-((2-(4-Fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)amino)benzonitrile

To a solution of4-((2-(4-flurophenyl)-5,6-dimethoxypyridin-3-yl)amino)benzonitrile (35mg, 0.1 mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added borontribromide (0.5 ml of a 1.0 M solution in CH₂Cl₂). After addition wascompleted, the reaction mixture was stirred for 16 h at roomtemperature. Dichloromethane was removed from the reaction mixturefollowed by addition of HCl (3N). The resulting solid was filtered. Thesolid was redissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. Theorganic phase was then dried and evaporated under reduced pressure toafford a solid in 55% yield. ¹H NMR (300 MHz, CDCl₃) δ: 7.47 (d, J=8.1Hz, 1H), 7.38 (m, 2H), 7.05 (m, 2H), 6.88 (m, 2H), 6.67 (d, J=8.4 Hz,1H), 6.30 (d, J=7.2 Hz, 1H), 5.44 (bs, 1H).

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 5-bromo-6-(4-fluorophenyl)-2,3-dimethoxypyridine (185 mg,0.59 mmol, 4-cyanoaniline (104 mg, 0.88 mmol), Pd₂(dba)₃ (46 mg, 0.05mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (21 mg, 0.05mmol) and KO^(t)Bu (98 mg, 0.88 mmol) in 1,4-dioxane (4.0 ml) wasdegassed for 30 min. This mixture was heated to 105° C. and stirred for16 h. The reaction mixture was cooled to room temperature andpartitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl (1×).The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 25%EtOAc in hexane to give 35 mg of the desired product, yield: 17%. ¹H NMR(300 MHz, CDCl₃) δ: 7.58-7.52 (m, 2H), 7.29-7.11 (m, 6H), 6.8-6.77 (m,1H), 4.16 (s, 3H), 3.95 (s, 3H).

Example 53 Preparation of Compound

5-(3-(1H-Tetrazol-5-yl)phenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added5-(3-cyanophenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one (48 mg,0.141 mmol), DMF (2.0 ml), NaN₃ (41 mg, 0.628 mmol) followed by AcOH(1.0 ml). The resulting mixture was heated to 120° C. for 4 h. After thecompletion of the reaction, the solvent was removed under reducedpressure. Addition of 3N HCl and stirring produced a solid which wasfiltered to give the pure product (35 mg, 63% yield). ¹H NMR (300 MHz,DMSO-d₆) δ: 9.45 (bs, 1H), 7.92-7.81 (m, 2H), 7.36 (t, 1H), 7.20 (m,2H), 7.07 (m, 2H), 6.88 (s, 1H).

Example 54 Preparation of Compound

3-(2-(4-Fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile

To a solution of5-(3-cyanophenyl)-6-(4-fluorophenyl)-2,3-dimethoxypyridine (114 mg, 0.34mmol) in CH₂Cl₂ (2.0 ml) under nitrogen, was added boron tribromide (1.5ml of a 1.0 M solution in CH₂Cl₂). After addition was completed, thereaction mixture was stirred for 20 h at room temperature.Dichloromethane was removed from the reaction mixture followed byaddition of HCl (3N). The resulting solid was filtered. The solid wasredissolved in CH₂Cl₂ and washed with NaHCO₃ and brine. The organicphase was then dried and evaporated under reduced pressure to afford thecrude product which was purified in ISCO using 5% MeOH in DCM to furnishthe pure product (95 mg) as white solid, yield: 91%. ¹H NMR (300 MHz,DMSO-d₆) δ: 7.57 (s, 1H), 7.47 (s, 1H), 7.40 (m, 2H), 7.25 (m, 2H), 7.08(m, 3H).

The requisite intermediate was prepared as follows

a. Preparation of Compound

A mixture of 6-bromo-5-(3-cyanophenyl)-2,3-dimethoxypyridine (150 mg,0.47 mmol), 4-fluorophenylboronic acid (99 mg, 0.70 mmol), Pd(PPh₃)₄ (70mg, 0.06 mmol) and K₂CO₃ (129 mg, 0.94 mmol) in 1,4-dioxane (3.0 ml) andH₂O (1.0 ml) was degassed for 30 min. This mixture was heated to 100° C.and stirred for 16 h. The reaction mixture was cooled to roomtemperature and partitioned between NaHCO₃ and EtOAc (3×), and washedwith NaCl (1×). The organic phase was dried over Na₂SO₄ and wasconcentrated. The resulting residue was purified by ISCO flashchromatography using 25% EtOAc in hexane to give 114 mg (74% yield)desired product. LC/MS: 335 (M+H).

Example 55 Preparation of Compound

3-(2-(4-Fluorophenyl)-5-hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzoicacid

To a solution of 5(3-benzoate)-6-(4-fluorophenyl)-2,3-dimethoxypyridine(90 mg, 0.245 mmol) in DCM (3.0 ml) under nitrogen, boron tribromide(1.5 ml of 1.0 M solution in CH₂Cl₂) was added. After addition wascompleted, the reaction mixture was refluxed for 16 h. The solvent wasremoved from the reaction mixture and the resulting solid was purifiedin ISCO using 10% MeOH in DCM with 1% acetic acid to furnish the pureproduct (45 mg) yield: 56%. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.74 (d, J=7.2Hz, 1H), 7.60 (s, 1H), 7.33 (t, 1H), 7.26-7.08 (m, 5H), 6.85 (s, 1H).

The requisite intermediates were prepared as follows

a. Preparation of Compound

A mixture of 6-bromo-5-(3-benzoate)-2,3-dimethoxypyridine (100 mg, 0.28mmol), 4-fluorophenylboronic acid (60 mg, 0.43 mmol), Pd(PPh₃)₄ (46 mg,0.04 mmol) and K₂CO₃ (77 mg, 0.56 mmol) in 1,4-dioxane (3.0 ml) and H₂O(1.0 ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 15%EtOAc in hexane to give 96 mg (92% yield) desired product. ¹H NMR (300MHz, CDCl₃) δ: 8.15-8.09 (m, 2H), 7.50-7.41 (m, 3H), 7.08-7.02 (m, 3H),6.96-6.91 (m, 1H), 4.27 (s, 3H), 4.11 (s, 3H), 4.09 (s, 3H).

b. Preparation of Compound

To a solution of 2,3-dimethoxy-5-(3-carbomethoxyphenyl)pyridine (500 mg,1.83 mmol) in acetic acid (4.5 ml) was added sodium acetate (746 mg, 5.5mmol). The reaction mixture was cooled to 0° C. and Br₂ (0.1 ml) inacetic acid (1.0 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 6 h. To this mixture 25% NaOH was addedat 0° C. until pH 6 and then extracted with dichloromethane three times.Organic layer wad dried, concentrated under reduced pressure andpurified by ISCO using 100% DCM to afford pure product 210 mg, yield:32%.

c. Preparation of Compound

A mixture of 5-bromo-2,3-dimethoxypyridine (520 mg, 2.39 mmol),3-carbomethoxyphenylboronic acid (560 mg, 3.12 mmol), Pd(PPh₃)₄ (346 mg,0.3 mmol) and K₂CO₃ (657 mg, 4.76 mmol) in 1,4-dioxane (5.0 ml) and H₂O(1.5 ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using DCM togive 540 mg (83% yield) desired product. ¹H NMR (300 MHz, CDCl₃) δ: 8.21(s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.73 (d, J=6.6Hz, 1H), 7.52 (t, 1H), 7.27 (d, J=1, 2 Hz, 1H), 4.07 (s, 3H), 3.96 (s,3H), 3.95 (s, 3H).

Example 56 Preparation of Compound

To a solution of2-([1,1′-biphenyl]-3-yl)-3-(4-fluorophenyl)-5,6-dimethoxypyridine (182mg, 0.46 mmol) in DCM (3.0 ml) under nitrogen, boron tribromide (1.5 mlof 1.0 M solution in CH₂Cl₂) was added. After addition was completed,the reaction mixture was stirred at room temperature overnight. Thesolvent was removed from the reaction mixture and it was redissolved inDCM. The organic layer was washed with water, sodium bicarbonatefollowed by brine. After drying with sodium sulfate, the solvent wasremoved under vacuum and the resulting residue was purified in ISCOusing 100% ethyl acetate to furnish the pure product (45 mg), yield:27%.

The requisite intermediates were prepared as follows

a. Preparation of Compound

To a solution of 6-bromo-5-(4-fluorophenyl)-2,3-dimethoxypyridine (300mg, 0.96 mmol) in THF (10 ml) was added n-BuLi (0.96 ml, 1.6 M inhexane) drop-wise at −78° C. The reaction mixture was stirred for 30minutes at this temperature after which [1,1′-biphenyl]-3-carbaldehyde(262 mg, 1.44 mmol) in THF (2.0 ml) was added. The reaction mixture wasfurther stirred for 30 minutes after which it was poured into ice-water(8.0 ml). Extraction with ethyl acetate, the organic layers were dried,evaporated and the crude product is further purified by ISCO using 25%ethyl acetate in hexane to afford the pure product (306 mg), yield: 76%.

b. Preparation of Compound

To a solution of[1,1-biphenyl]-2-yl(3-(4-flurorphenyl)-5,6-dimethoxypyridin-2-yl)methanol(323 mg, 0.56 mmol) in DCE (8.0 ml) was added TFA (1.0 ml) and Et₃SiH(130 mg, 1.12 mmol) at 0° C. under N₂. The reaction mixture was heatedat 80° C. for 3 h after which the solvents are removed and the residuewas dissolved in ethyl acetate. The organic layer after washed withNaHCO₃ and brine was dried, evaporated and the crude product waspurified by ISCO using 30% EtOAc in hexane to afford the pure product(186 mg), yield: 83%.

Example 57 Preparation of Compound

5-(4-Fluorobenzyl)-3-hydroxypyridin-2(1H)-one

To a solution of 5-(4-fluorobenzyl)2,3-dimethoxypyridine (25 mg, 0.1mmol) in CH₂Cl₂ (3.0 ml) under nitrogen, was added boron tribromide (1.0M solution in CH₂Cl₂) (0.3 ml). After addition was completed, thereaction mixture was stirred for 16 h at room temperature. The solventwas removed from the reaction mixture and the residue was redissolved inCH₂Cl₂. The organic layer was washed with NaHCO₃ and brine, dried usinganhydrous sodium sulfate and evaporated under reduced pressure to afforda crude solid which was further purified using 10% MeOH in DCM to affordthe desired product (12 mg), yield: 54%. ¹H NMR (300 MHz, MeOD-d₄) δ:7.11 (m, 2H), 6.92 (m, 2H), 6.63 (d, J=9.9 Hz, 2H), 3.60 (s, 2H).

The requisite intermediates were prepared as follows

a. Preparation of Compound

To a solution of 5-bromo-2,3-dimethoxypyridine (217 mg, 1.0 mmol) in THF(6.0 ml) was added at −78° C. under argon a solution of n-BuLi (2 ml,1.6 M solution in hexane). After stirring for 1 h at this temperatureanhydrous DMF (0.4 ml) was added and the reaction was stirred for anadditional 30 min. The reaction was quenched by the addition of Sat.NH₄Cl and was extracted with ethyl acetate three times. Combined organiclayers were dried in sodium sulfate and after the removal of the solventthe crude product was purified by ISCO using 20% EtOAc in hexane toafford the pure product (52 mg), yield: 31%. ¹H NMR (300 MHz, CDCl₃) δ:9.94 (s, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 4.12 (s, 3H), 3.94 (s, 3H).

b. Preparation of Compound

A solution of 4-fluorophenyl magnesium bromide (3 ml, 1.0 M in THF) wasadded to a solution of 5-formyl-2,3-dimethoxypyridine (220 mg, 1.32mmol) in Et₂O (30 ml) keeping the internal temperature at −40° C. for 1h. The reaction was allowed to warm to 0° C. and was quenched with theaddition of sat. NH₄Cl. The mixture was extracted with ether and thecombined organic layers were washed with water and brine to afford thepure product (330 mg), yield: 95%. ¹H NMR (300 MHz, CDCl₃) δ: 7.52 (s,1H), 7.27-7.22 (m, 2H), 6.98-6.92 (m, 3H), 5.66 (s, 1H), 3.91 (s, 3H),3.73 (s, 3H).

c. Preparation of

To a solution of (5,6-dimethoxypyridin-3-yl)(4-fluorophenyl)methanol (75mg, 0.28 mmol) in DCM (5.0 ml) was added TFA (2 drops) and Et₃SiH (66mg) at 0° C. under N₂. The reaction mixture was stirred at roomtemperature for 18 h after which the solvents are removed and theresidue was redissolved in DCM. The combined organic layers after washedwith NaHCO₃ and brine was dried, evaporated and the crude product waspurified by ISCO using 20% EtOAc in hexane to afford the pure product(40 mg), yield: 58%. NMR (300 MHz, CDCl₃) δ: 7.58 (s, 1H), 7.16-7.11 (m,2H), 7.01-6.96 (m, 2H), 6.80 (s, 1H), 4.08 (s, 3H), 3.88 (s, 3H), 3.81(s, 3H).

Example 58 Preparation of Compound

5-(4-Fluorophenyl)-6-[4-(1H-tetrazol-5-yl)phenyl]-3-hydroxypyridin-2(1H)-one

To a sealed tube equipped with a small stirring bar was added5-(4-fluorophenyl)-6-(4-cyanophenyl)-3-hydroxypyridin-2(1H)-one (50 mg,0.16 mmol), DMF (2.0 ml), NaN₃ (42 mg, 0.64 mmol) followed by AcOH (1.0ml). The resulting mixture was heated to 120° C. overnight. Aftercompletion of the reaction, the solvent was removed under vacuum.Addition of 1N HCl and stirring produced a solid which was filtered togive the pure product (30 mg, 54% yield). ¹H NMR (300 MHz, DMSO-d₆) δ:7.83 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.09-7.00 (m, 4H), 6.81(s, 1H). HRMS Calcd for C₁₈H12FN₅O₂ (M+H)⁺ 350.1048. Found 350.1058.

Example 59 Preparation of Compound

To a solution of bis-5,6-dimethyl benzoate-2,3-dimethoxypyridine (116mg, 0.285 mmol) in DCM (3.0 ml) under nitrogen, boron tribromide (1.5 mlof 1.0 M solution in CH₂Cl₂) was added. After addition was completed,the reaction mixture was stirred for 16 h. The solvent was removed fromthe reaction mixture and the resulting solid was redissolved in ethylacetate and the organic layer was washed with sodium bicarbonate. Theaqueous layer was acidified to pH 1 and was extracted with ethylacetate. The combined organic layers was dried and the solvent wasremoved to afford the pure product (68 mg), yield: 68%. NMR (300 MHz,DMSO-d₆) δ: 9.56 (bs, 1H), 7.83-7.76 (m, 3H), 7.28 (d, J=8.4 Hz, 2H),7.16 (d, J=8.1 Hz, 2H), 6.88 (s, 1H).

The requisite intermediate was prepared as follows

a. Preparation of Compound

4,4′-(5-hydroxy-6-oxo-1,6-dihydropyridine-2,3-diyl)dibenzoic acid

A mixture of 5,6-dibromo-2,3-dimethoxypyridine (400 mg, 1.8 mmol),4-acetoxyphenylboronic acid (648 mg, 3.6 mmol), Pd(PPh₃)₄ (415 mg, 0.36mmol) and K₂CO₃ (993 mg, 7.0 mmol) in 1,4-dioxane (6.0 ml) and H₂O (2.0ml) was degassed for 30 min. This mixture was heated to 100° C. andstirred for 16 h. The reaction mixture was cooled to room temperatureand partitioned between NaHCO₃ and EtOAc (3×), and washed with NaCl(1×). The organic phase was dried over Na₂SO₄ and was concentrated. Theresulting residue was purified by ISCO flash chromatography using 15%EtOAc in hexane to give 120 mg (17% yield) desired product. LC/MS: 408.

Example 60 Protein Expression, Purification, and Crystallization

Pandemic 2009 H1N1 influenza A endonuclease (residues 1-204) wasexpressed in BL21 (RIL) cells (Stratagene). The BL21 cells were grown toan OD₆₀₀ of 0.8 and induced with 0.2 mM IPTG at 17 degrees Celsius for17 hours. Cells were harvested by centrifugation and purified on Ni-NTA(Qiagen) according to the manufacturers recommendations. The dualhexa-His tag was then removed by 3C protease cleavage. S2C was furtherpurified by size exclusion chromatography using HiLoad 26/60 Superdex 75(GE Heathcare). The buffer used for size exclusion and the final bufferfor storage of the protein was 100 mM NaCl and 20 mM Tris pH 8.0. Theprotein was concentrated to 10 mg/ml using a Ultrafree 10K (Millipore),aliquoted and stored at −80 degrees Celsius.

Crystals were formed by mixing in a 1:1 ratio endonuclease (5 mg/ml)with crystallization buffer containing 200 mM MES pH 6.7, 27% (w/v)PEG8000, 200 mM ammonium sulfate, 1 mM manganese chloride, 10 mMmagnesium acetate, 10 mM taurine and 50 mM sodium fluoride. Trays werestored at 20 degrees Celsius and crystals formed within a few hours andgrew to maximum size in one to two weeks.

Example 61 Compound Soaking, Data Collection, and Processing

Crystal structure and modeling studies were carried out for improvinginfluenza A inhibition and specificity of the compounds derived fromformula I (Bauman et al.; ACS Chem Bio. 2013; Epub Aug. 26, 2013). Mostsoaks of ligands were performed by taking crystals and by step-wisegradient shifting the surrounding crystallization solution to 1 mMmanganese sulfate, 200 mM HEPES pH 7.7, 25% (w/v) PEG 8000, 50 mMammonium sulfate, 5 mM magnesium acetate, and 10% (v/v) ethylene glycol.80-100 mM L-arginine was included to improve solubility of thecompounds. Crystals were then soaked with the ligand for 2-17 hours at20 degrees Celsius before placing into liquid nitrogen for storage.X-ray diffraction data collection was performed at the Cornell HighEnergy Synchrotron Source (CHESS) F1 beamline and the NationalSynchrotron Light Source (NSLS) beamlines X25 and X29. The diffractiondata were indexed, processed, scaled and merged using HKL2000(Otwinowski et al., Meth Enzymol. 1997; 276:307-26). Datasets containingbound fragments were further processed using CCP4 (Winn et al.; ActaCryst. 2011; D67:235-42) and PHENIX (Afonine et al.; Acta Cryst. 2012;D68:352-67).

X-ray crystal structures of I and derivatives in complex with 2009 H1N1influenza A endonuclease enzyme revealed a novel mode of chelation ofthe compounds to two metal ions (Mg²⁺ or Mn²⁺ at the positions M1 andM2) at the active site. Structures and subsequent modeling suggestedpossibilities of chemical substitutions at positions 4, 5 and 6.

A wide variety of substituents can be accommodated at the positions 5and 6. Steric factors with influenza endonuclease appear to constrainthe number of substituents that are well tolerated at the 4-position.The presence of a 6-phenyl substituent tends to significantly increasethe accommodation of more varied substituents at the 5-position and to alesser extent at the 4-position. Some of the predicted derivatives of Ihave been synthesized and tested for inhibition of influenza Aendonuclease activity (Example 63). X-ray crystal structures ofderivatives of I were determined in complex with 2009 H1N1 influenza Aendonuclease enzyme for deriving effective 3D SAR that guided futuresynthesis cycles.

The ability of a compound to inhibit endonuclease activity can beevaluated using known assays or using the assay described in Example 62.The novel assay described in Example 62 represents part of theinvention.

Example 62 Endonuclease Assay

The PA_(N) domain has been shown to cleave ssRNA as well as ssDNA. Todemonstrate the inhibition of endonuclease cleavage by PA_(N), a highthroughput assay was developed (U.S. patent application Ser. No.13/554,709; Sagong et al.; ACS Med Chem Lett. 2013; 4(6): 547-550). ATaqMan-like oligonucleotide was used containing a 6-carboxy-fluorescein(FAM) fluorophore at the 5′-end followed by 19 nucleotides and a minorgroove binding non-fluorescent quencher (MGBNFQ, Applied Biosystems) atthe 3′-end. When excited by light at a wavelength of 488 nm, MGBNFQquenches the fluorescence of FAM via fluorescence resonance energytransfer. If the endonuclease cleaves the oligonucleotide, the quencheris no longer coupled to the fluorophore, and therefore, FAM fluoresces.This assay can be performed in a high-throughput (e.g. 96 well plate)format. The assay can be used to evaluate the inhibitory characteristicsof compounds that are found to bind PA_(N) and to screen libraries ofdrug-like compounds. The assay uses the probe6FAM-TGGCAATATCAGCTCCACA-MGBNFQ

The assay can be performed in a 40 μl reaction volume with 50 mM Tris pH7.5, 50 mM NaCl, 1 mM MgSO₄, 0.05 mM MnSO₄, 1 mM DTT, 0.75 mM CHAPS, 50nM probe, and 25 nM endonuclease.

The reaction mixture is set up as a master mix with the buffer, probe,and protein on ice. The inhibitor is then added to a maximum DMSOconcentration of 2.5% (v/v) and serial dilutions are made on ice.Varioskan Fluorometer (Thermo Scientific), set to an excitation of 488nm and emission of 518 nm, is used to measure the fluorescence of thesamples at 37 degrees Celsius. Fluorescence is measured at various timepoints (5, 120, and 240 minutes) during the 37 degrees Celsiusincubation. Activity/inhibition is calculated based on the change influorescence over time using Prism Graphpad non-linear regressionanalysis.

Data for representative compounds of formula I in the endonucleaseinhibition assay described above is provided in the following table.

IC₅₀ (uM) using either 500 nM or 50 nM Chemical Name Structure enzyme5-Chloro-3-hydroxypyridin- 2(1H)-one

5.0 5-Bromo-3-hydroxypyridin- 2(1H)-one

5.0 6-(4-Fluoro-phenyl)-3- hydroxypyridin-2(1H)-one

0.43 6-(4-(tert-Butyl)phenyl)-3- hydroxypyridin-2(1H)-one

1.6 3-Hydroxy-6-(4- (trifluoromethyl)phenyl)pyridin- 2(1H)-one

0.4 3-Hydroxy-6-phenylpyridin- 2(1H)-one

0.38 3-Hydroxy-6-(4- methoxyphenyl)pyridin-2(1H)- one

1.2 6-(3-Fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.53 6-(3-Methoxyphenyl)-3- hydroxypyridin-2(1H)one

0.54 6-(Cyclohex-1-en-1-yl)-3- hydroxypyridin-2(1H)-one

0.75 6-(3,4-Dihydroxyphenyl)-3- hydroxypyridin-2(1H)-one

0.60 6-Cyclohexyl-3- hydroxypyridin-2(1H)-one

2.5 5,6-bis(4-Fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.041 5,6-bis(3-Fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.044 5,6-bis(phenyl)-3- hydroxypyridin-2(1H)-one

0.047 3-Hydroxy-5,6-bis(4- nitrophenyl)pyridin-2(1H)-one

0.72 4,4′-(6-Oxo-1,6- dihydropyridine-2,3-diyl)- dibenzamide

0.23 3,3′-(6-Oxo-1,6- dihydropyridine-2,3-diyl)- dibenzamide

0.11 5,6-Dibromo-3-hydroxypyridin- 2(1H)-one

1.5 6-Bromo-5-(4-fluorophenyl)-3- hydroxypyridin-2(1H)-one and5-Bromo-4-(4-fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.187 6-Bromo-5-(3-fluorophenyl)-3- hydroxypyridin-2(1H)-one and6-Bromo-5-(3-fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.36 5-(4-Fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.73 6-Bromo-5-(4-fluorophenyl)-3- hydroxypyridin-2(1H)-one

4.2 5-Bromo-6-(3-fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.15 6-(4-Fluorophenyl)-5- hydroxypyrimidin-4(3H)-one

193 2-(4-Fluorophenyl)-5- hydroxypyrimidin-4(3H)-one

0.58 4-(5-Hydroxy-6-oxo-1,6- dihydropyrimidin-2- yl)benzonitrile

0.52 2-(4-(1H-Tetrazol-5-yl)phenyl)- 5-hydroxypyrimidin-4(3H)-one

0.15 3-(5-Hydroxy-6-oxo-1,6- dihydropyrimidin-2- yl)benzonitrile

0.25 2-(3-(1H-Tetrazol-5-yl)phenyl)- 5-hydroxypyrimidin-4(3H)-one

0.48 5-(4-Fluorophenyl)-4- hydroxypyridazin-3(2H)-one

>200 6-(4-Fluorophenyl)-4- hydroxypyridazin-3(2H)-one

6.0 4-(5-Hydroxy-6-oxo-1,6- dihydropyridazin-3- yl)benzonitrile

9.3 6-(4-(1H-Tetrazol-5-yl)phenyl)- 4-hydroxypyridazin-3(2H)-one

3.0 5-Cyclohexyl-3- hydroxypyridin-2(1H)-one

2.1 5-[3-(1H-Tetrazol-5-yl)phenyl]- 3-hydroxypyridin-2(1H)-one

0.85 3-(5-Hydroxy-6-oxo-1,6- dihydropyridin-3-yl)benzoic acid

1.79 5-(3-Fluorophenyl-3- hydroxypyridin-2(1H)-one

0.74 4-(5-Hydroxy-6-oxo-1,6- dihydropyridin-3-yl)benzoic acid

0.51 3,3′-(5-Hydroxy-6-oxo-1,6- dihydropyridine-2,3- diyl)dibenzoic acid

0.70 5-Phenyl-3-hydroxypyridin- 2(1H)-one

>10 5-(p-Cyanophenyl-3- hydroxypyridin-2(1H)-one

6.07 5-[4-(1H-Tetrazol-5-yl)phenyl]- 3-hydroxypyridin-2(1H)-one

0.37 6-(4-Cyanophenyl-3- hydroxypyridin-2(1H)-one

1.2 6-[4-(1H-tetrazol-5-yl)phenyl]- 3-hydroxypyridin-2(1H)-one

0.85 5,6-bis(4-Cyanophenyl)-3- hydroxypyridin-2(1H)-one

0.10 5,6-bis[4-(1H-Tetrazol-5- yl)phenyl]-3-hydroxypyridin- 2(1H)-one

0.29 5-(4-Fluorophenyl)-6-(4- cyanophenyl)-3- hydroxypyridin-2(1H)-one

0.054 5-(4-Cyanophenyl)-6-(4- fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.136 5-[4-(1H-Tetrazol-5-yl)phenyl]- 6-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

0.011 5,6-bis(4-Fluorophenyl)-3- hydroxypyridin-2(1H)-one

0.176 5,6-Diphenyl-3-hydroxypyridin- 2(1H)-one

0.12 4-((2-(4-Fluorophenyl)-5- hydroxy-6-oxo-1,6- dihydropyridin-3-yl)amino)benzonitrile

1.0 5-(3-(1H-Tetrazol-5- yl)phenyl)-6-(4- fluorophenyl)-3-hydroxypyridin-2(1H)-one

0.034 3-(2-(4-Fluorophenyl)-5- hydroxy-6-oxo-1,6- dihydropyridin-3-yl)benzonitrile

0.049 3-(2-(4-Fluorophenyl)-5- hydroxy-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

0.035 6-([1,1′-Biphenyl]-4-ylmethyl)- 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

0.12 5-(4-Fluorobenzyl)-3- hydroxypyridin-2(1H)-one

8.6 6-(4-(1H-Tetrazol-5-yl)phenyl)- 5-(4-fluorophenyl)-3-hydroxypyridin-2(1H)-one

0.018 4,4′-(5-hydroxy-6-oxo-1,6- dihydropyridine-2,3- diyl)dibenzoicacid

0.90

The anti-influenza activity of a compound of the invention can beevaluated using the assay described in Example 63.

Example 63 Anti-Influenza Activity

Anti-influenza activity of the compounds can be tested as previouslydescribed (Bauman et al.; ACS Chem Bio. 2013; Epub 8/26/13).

Madin-Darby canine kidney (MDCK) cells were maintained in Dulbecco'smodified Eagle's medium (DMEM) supplemented with 10% (v/v) fetal bovineserum (FBS), and 1% (w/v) penicillin, 100 units mL⁻¹; streptomycin, 100μg mL⁻¹; L-glutamine, 2 mM (P-S-G) at 37° C. in a 5% CO₂ atmosphere.After viral infections, cells were maintained in DMEM containing 0.3%(w/v) bovine serum albumin (BSA), 1% (w/v) P-S-G, and 1.0 μg mL⁻¹tosyl-sulfonyl phenylalanyl chloromethyl ketone (TPCK)-treated trypsin(Sigma).

Influenza A/Puerto Rico/8/1934 (H1N1; PR8)(Schickli et al.; Phil Tans RSoc B. 2001; 356:1965-1973) was prepared from infected MDCK cells asdescribed previously (Martinez-Sobrido et al.; J Virol. 2010;84:2157-2163). To determine inhibition of 7, confluent monolayers ofMDCK cells (12-well plate format, 10⁶ cells) were infected in triplicatefor 1 hour at room temperature with PR8 at low multiplicity of infection(moi, 0.001). After infection, cells were incubated at 37° C. with 0.1%(v/v) DMSO in the absence or presence of 7 or oseltamivir. Virus titersin tissue culture supernatants at 24 hours post infection weredetermined by immunofocus assay (fluorescent forming units, FFU) in MDCKcells (Baker et al.; J Virol. 2013; 87:8591-8605). Briefly, triplicatewells of MDCK cells (96-well format, 4×10⁴ cells) were infected with10-fold serial dilutions of tissue culture supernatants. Ten hours postinfection, presence of virus was detected by immunofluorescence with aninfluenza NP monoclonal antibody (HT103). Mean value and standarddeviations were calculated using GraphPad Prism 6.0b software.

Cytotoxity of compounds can be determined as described. Triplicate, 50%confluent monolayers of MDCK cells (96-well format, 2×10⁴ cells) wereincubated in media containing 0.1% (v/v) DMSO in the absence or presenceof the indicated drugs for 24 hours. Cytotoxicity was then determined byCellTiter96 assay (Promega) by reading absorbance of formazan product at570 nm (Vmax kinetic microplate reader, Molecular Devices).

Viral yield inhibition assay and cytotoxicity assay. Virus yield assayusing MDCK cells and the A/Puerto Rico/8/1934 (H1N1) influenza strainwas used to determine the antiviral activity of for6-(4-fluorophenyl)-3-hydroxy-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-1H-pyridin-2-one;oseltamivir and 0.1% (v/v) DMSO (only) were used as the positive andnegative controls. Cytotoxicity for6-(4-fluorophenyl)-3-hydroxy-5-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]-1H-pyridin-2-one(shown in grey) was determined from MDCK cells after 24 hours using theMTT assay. Results are shown in FIG. 1.

Example 64 Inhibition of HIV-1 Integrase

The two metal binding motif of these compounds allows for potentialcross reactivity with other drug targets with two metal containingactive sites. Compounds were tested for LEDGF independent integration(strand transfer) and 3′ processing based on established protocols(Kessl et al.; J Biol Chem, 2012; 287:16801-16811).

The 3′-processing was assayed using blunt ended ³²P-labled 21-mersynthetic double stranded U5 DNA. The strand transfer assay used³²P-labled recessed end 19-mer synthetic double stranded U5 DNA. 500 nMintegrase was pre-incubated with compound for 30 minutes on ice in 50 mMMOPS (pH 7.2) buffer containing 2 mM β-mercaptoethanol, 50 mM NaCl and10 mM MgCl₂. 50 nM DNA substrate was added to the reaction and incubatedat 37° C. for 1 hour when the reactions were stopped with 50 mM EDTA.The reaction products are subjected to denaturing polyacrylamide gelelectrophoresis and visualized using a Storm 860 Phosphorimager(Amersham Biosciencs). The ICs₅₀s of representative compounds of formula(I) as detected with a LEDGF independent integration assay or a3′-processing assay are shown in the following table.

IC₅₀ (μM) Strand IC₅₀ (μM) Structure Transfer 3′-Process

 6.0 ± 0.8  8.2 ± 2.5

11.7 ± 1.5 20.8 ± 5.8

15.7 ± 0.9 11.6 ± 1.6

20.5 ± 1.3 22.2 ± 2.5

23.7 ± 2.7 12.6 ± 3.2

50.7 ± 2.9  7.4 ± 1.6

Example 65 Binding to HIV-1 RNase H

RT constructs RT52A (crystallization optimized mutant) were constructed,expressed, and purified as described previously. (Bauman et al. Nucl.Acids Res, 2008; 36: 5083-5092)). Prior to crystallization, RT52A (20mg/ml) was incubated with rilpivirine (TMC278/Edurant) at 1:1.5 molarprotein to drug ratio at room temperature (˜23° C.) for 30 minutes.RT52A-rilpivirine crystals were produced in hanging drops at 4° C. witha 1:1 ratio of protein and well solution containing 11% PEG 8000, 4% PEG400, 50 mM imidazole pH 6.6, 10 mM spermine, 15 mM MgSO₄, 100 mMammonium sulfate, and 5 mM tris(2-carboxyethyl)-phosphine and anexperimentally optimized concentration of microseeds from previouslygenerated crystals (preseeding).

The compound/cryo soaking solutions were prepared with crystallizationwell solution with the addition of 80 mM L-arginine, 5% (v/v) ethyleneglycol, 1 mM MnSO₄ and 20% (v/v) d₆-DMSO (containing 20 mM finalconcentration of 5-bromopyridine-2,3-diol). Crystals ofRT52A-rilpivirine were harvested two weeks to four months after crystalsformed. The crystals were placed in compound/cryo soaking drops for oneto two minutes before flash cooling in liquid nitrogen. Data collectionwas performed at the Cornell High Energy Synchrotron Source (CHESS) F1beamlin. The diffraction data were indexed, processed, scaled and mergedusing HKL2000I.³⁹ Initial datasets from crystals were collected tominimize the time of collection by increasing the oscillation range perimage and decreasing exposure time. F_(o)-F_(o) maps (as describedpreviously) were immediately calculated using CNS and visualized withCoot.^(41, 42) Datasets for crystals containing bound fragments werethan recollected to improve maximum X-ray diffraction resolution.High-resolution datasets containing bound fragments were further refinedusing PHENIX and Coot.^(40, 41) Crystal structure figures were made withMacPyMol (Schrödinger, New York, N.Y.). Results are shown in FIG. 3.

Example 66

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula I:

wherein: X¹ is CR₅ and X² is CR₆; or X¹ is N and X² is CR₆; or X¹ is CR₅and X² is N; R₄ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b),—N(R^(y))S(O)_(n)R^(c), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₄ is optionally substituted with one ormore groups independently selected from R_(n); R₅ is H, halo, cyano,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, aryl, heteroaryl, heterocycle, —NR^(a)R^(b),—S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b), —COOR^(c),or —CONR^(a)R^(b), wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle of R₅ is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl, heterocycle, and heteroaryl of R₅ is optionallysubstituted with one or more groups independently selected from R_(n);R₆ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₆ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle and heteroaryl of R₆ is optionally substituted with one ormore groups independently selected from R_(n); each R^(a) and R^(b) isindependently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, (C₃-C₁₂)carbocycle, aryl, andheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and(C₃-C₁₂)carbocycle of R^(a) and R^(b) is optionally substituted with oneor more groups independently selected from R_(m); and wherein each aryland heteroaryl of R^(a) and R^(b) is optionally substituted with one ormore groups independently selected from R_(n); each R^(c) isindependently selected from hydrogen, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(c) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(c) is optionally substitutedwith one or more groups independently selected from R_(n); each R^(e)and R^(f) is independently selected from hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl; and each R^(g) isindependently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, (C₃-C₁₂)carbocycle, aryl, andheteroaryl; each R_(m) is independently selected from cyano, halo,nitro, hydroxy, oxo, carboxy, aryl, heteroaryl, heterocycle, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each heterocycle of R_(m) is optionallysubstituted with one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, cyano, halo, nitro, hydroxy, oxo, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); and wherein eacharyl and heteroaryl of R_(m) is optionally substituted with one or moregroups independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, cyano, halo, nitro,hydroxy, carboxy, R_(m1), aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, —COOR^(g), and —CONR^(e)R^(f); eachR_(m1) is independently selected from aryl and heteroaryl, wherein anyaryl and heteroaryl of R_(m1) is optionally substituted with one or moregroups independently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, heterocycle, aryl,heteroaryl, cyano, halo, nitro, hydroxy, carboxy, —NR^(e)R^(f),—S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f),(C₁-C₆)alkoxy, —COOR^(g), and —CONR^(e)R^(f); each R_(n) isindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, heterocycle, and (C₃-C₁₂)carbocycle ofR_(n) is optionally substituted with one or more groups independentlyselected from cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); wherein each aryland heteroaryl of R_(n) is optionally substituted with one or moregroups independently selected from cyano, halo, nitro, hydroxy, oxo,carboxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, and —CONR^(e)R^(f); each R^(y) isindependently selected from hydrogen and (C₁-C₆)alkyl; and n is 0, 1, or2; or a salt or prodrug thereof.
 2. The compound of claim 1 wherein X¹is CR₅ and X² is CR₆.
 3. The compound of claim 1 which is a compound offormula Ia:

wherein: R₄ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b),—N(R^(y))S(O)_(n)R^(c), —COOR^(e), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₄ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₄ is optionally substituted with one ormore groups independently selected from R_(n); R₅ is H, halo, cyano,nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, aryl, heteroaryl, heterocycle, —NR^(a)R^(b),—S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b), —COOR^(c),or —CONR^(a)R^(b), wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle of R₅ is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl, heterocycle, and heteroaryl of R₅ is optionallysubstituted with one or more groups independently selected from R_(n);R₆ is H, halo, cyano, nitro, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c),—S(O)_(n)NR^(a)R^(b), —COOR^(c), or —CONR^(a)R^(b), wherein each(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle of R₆ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl,heterocycle, and heteroaryl of R₆ is optionally substituted with one ormore groups independently selected from R_(n); each R^(a) and R^(b) isindependently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, (C₃-C₁₂)carbocycle, aryl, andheteroaryl, wherein each (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and(C₃-C₁₂)carbocycle of R^(a) and R^(b) is optionally substituted with oneor more groups independently selected from R_(m); and wherein each aryland heteroaryl of R^(a) and R^(b) is optionally substituted with one ormore groups independently selected from R_(n); each R^(c) isindependently selected from hydrogen, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl, wherein each (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, and (C₃-C₁₂)carbocycle of R^(c) is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl of R^(c) is optionally substitutedwith one or more groups independently selected from R_(n); each R^(e)and R^(f) is independently selected from hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,(C₃-C₁₂)carbocycle, aryl, and heteroaryl; and each R^(g) isindependently selected from hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkanoyl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, (C₃-C₁₂)carbocycle, aryl, andheteroaryl; each R_(m) is independently selected from cyano, halo,nitro, hydroxy, oxo, carboxy, aryl, heteroaryl, heterocycle, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each heterocycle of R_(m) is optionallysubstituted with one or more groups independently selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, cyano, halo, nitro, hydroxy, oxo, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); wherein each aryland heteroaryl of R_(m) is optionally substituted with one or moregroups independently selected from cyano, halo, nitro, hydroxy, carboxy,aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy, —NR^(e)R^(f),—S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f),(C₁-C₆)alkoxy, —COOR^(g), and —CONR^(e)R^(f); each R_(n) isindependently selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl, heteroaryl,heterocycle, cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —S(O)_(n)NR^(e)R^(f), —COOR^(g), and—CONR^(e)R^(f); wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, heterocycle, and (C₃-C₁₂)carbocycle ofR_(n) is optionally substituted with one or more groups independentlyselected from cyano, halo, nitro, hydroxy, carboxy, aryloxy,heteroaryloxy, heterocycleoxy, —NR^(e)R^(f), —S(O)_(n)R^(g),—N(R^(y))S(O)_(n)R^(g), —COOR^(g), and —CONR^(e)R^(f); wherein each aryland heteroaryl of R_(n) is optionally substituted with one or moregroups independently selected from cyano, halo, nitro, hydroxy, oxo,carboxy, aryl, heteroaryl, aryloxy, heteroaryloxy, heterocycleoxy,—NR^(e)R^(f), —S(O)_(n)R^(g), —N(R^(y))S(O)_(n)R^(g), —COOR^(g),—S(O)_(n)NR^(e)R^(f), (C₁-C₆)alkoxy, and —CONR^(e)R^(f); each R^(y) isindependently selected from hydrogen and (C₁-C₆)alkyl; and n is 0, 1, or2; or a salt thereof. 4-12. (canceled)
 13. The compound of claim 1wherein R₅ is H, halo, (C₁-C₆)alkyl, (C₃-C₁₂)carbocycle, —NR^(a)R^(b),or aryl, wherein each (C₁-C₆)alkyl and (C₃-C₁₂)carbocycle is optionallysubstituted with one or more groups independently selected from R_(m);and wherein any aryl is optionally substituted with one or more groupsindependently selected from R_(n). 14-18. (canceled)
 19. The compound ofclaim 1 wherein R₅ is phenyl, benzyl, 2-pyridyl, 3-pyridyl, or 4-pyridylwherein the phenyl or pyridyl is optionally substituted with one or moregroups selected from the group consisting of —COOH, —CONR^(e)R^(f),—SO₃H, —SO₂NHCH₃, OH, OCH₃, F, Cl, Br, CH₃; or wherein R₅ is methylsubstituted with COOH, SO₃H, SO₂NHCH₃, OH, a CF₃ or a tetrazole.
 20. Thecompound of claim 1 wherein R₆ is H, halo, (C₁-C₆)alkyl,(C₃-C₁₂)carbocycle or aryl, wherein each (C₁-C₆)alkyl and(C₃-C₁₂)carbocycle is optionally substituted with one or more groupsindependently selected from R_(m); and wherein any aryl is optionallysubstituted with one or more groups independently selected from R_(n).21-24. (canceled)
 25. The compound of claim 1 wherein R₆ is H, bromo,phenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl,3-methoxyphenyl, 3-fluorophenyl, cyclohex-1-en-1-yl,3,4-dihydroxyphenyl, 4-cyclohexylphenyl, 4-nitrophenyl,3-aminocarbonylphenyl, or 4-aminocarbonylphenyl.
 26. The compound ofclaim wherein R₆ is phenyl or benzyl, which phenyl or benzyl isoptionally substituted with one or more substituents selected from thegroup consisting of F, Cl, Br, OCH₃, CH₃, and CONR^(e)R^(f).
 27. Thecompound of claim 1 wherein: R₅ is H, halo, cyano, nitro, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle, aryl,heteroaryl, heterocycle, —NR^(a)R^(b), —S(O)_(n)R^(c),—N(R^(y))S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b), —COOR^(c), or—CONR^(a)R^(b), wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₁₂)carbocycle of R₅ is optionallysubstituted with one or more groups independently selected from R_(m);and wherein each aryl and heteroaryl, of R₅ is optionally substitutedwith one or more groups independently selected from R_(n); and R₆ isbromo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy,(C₃-C₁₂)carbocycle, aryl, heteroaryl, heterocycle, —NR^(a)R^(b),—S(O)_(n)R^(c), —N(R^(y))S(O)_(n)R^(c), —S(O)_(n)NR^(a)R^(b), —COOR^(c),or —CONR^(a)R^(b), wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₂-C₆)alkoxy, and (C₃-C₁₂)carbocycle of R₆ isoptionally substituted with one or more groups independently selectedfrom R_(m); and wherein each aryl and heteroaryl, of R₆ is optionallysubstituted with one or more groups independently selected from R_(n).28. The compound of claim 1 wherein: R₅ is (C₁-C₃)alkyl, aryl,heteroaryl, wherein each (C₁-C₃)alkyl of R₅ is optionally substitutedwith one or more groups independently selected from R_(m); and whereineach aryl and heteroaryl of R₅ is optionally substituted with one ormore groups independently selected from R_(n); and R₆ is bromo,(C₁-C₃)alkyl, (C₃-C₈)carbocycle, aryl, heteroaryl, wherein each(C₁-C₆)alkyl, (C₃-C₁₂)carbocycle of R₆ is optionally substituted withone or more groups independently selected from R_(m); and wherein eacharyl and heteroaryl, of R₆ is optionally substituted with one or moregroups independently selected from R_(n).
 29. The compound of claim 1wherein: R₄ is H; R₅ is H, halo or aryl wherein each aryl of R₅ isoptionally substituted with one or more groups independently selectedfrom R_(n); R₆ is (C₃-C₁₂)carbocycle or aryl, wherein each(C₃-C₁₂)carbocycle of R₆ is optionally substituted with one or moregroups independently selected from R_(m); and wherein each aryl of R₆ isoptionally substituted with one or more groups independently selectedfrom R_(n).
 30. The compound of claim 1 wherein: R₄ is H; R₅ is H, haloor phenyl wherein each phenyl of R₅ is optionally substituted with oneor more groups independently selected from R_(n); R₆ is (C₆)carbocycleor phenyl, wherein each (C₆)carbocycle of R₆ is optionally substitutedwith one or more groups independently selected from R_(m); and whereineach phenyl of R₆ is optionally substituted with one or more groupsindependently selected from R_(n).
 31. The compound of claim 1 which is:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim1 which is:

or a pharmaceutically acceptable salt thereof.
 33. A pharmaceuticalcomposition comprising a compound of formula I as described in claim 1or a pharmaceutically salt or prodrug thereof, and a pharmaceuticallyacceptable diluent or carrier.
 34. A method to promote an antiviraleffect in an animal comprising administering a compound of formula I asdescribed in claim 1, or a pharmaceutically salt or prodrug thereof, tothe animal.
 35. A method to inhibit an endonuclease in an animal in needof such treatment comprising administering a compound of formula I asdescribed in claim 1, or a pharmaceutically salt or prodrug thereof, tothe animal.
 36. A method to inhibit an exonuclease in an animal in needof such treatment comprising administering a compound of formula I asdescribed in claim 1, or a pharmaceutically salt or prodrug thereof, tothe animal.
 37. A method to treat influenza in an animal comprisingadministering a compound of formula I as described in claim 1, or apharmaceutically salt or prodrug thereof, to the animal.
 38. A method totreat HIV in an animal comprising administering a compound of formula Ias described in claim 1, or a pharmaceutically salt thereof, to theanimal. 39-49. (canceled)